Hereditary paraganglioma targets diverse paraganglia.

Paragangliomas are highly vascularised and often heritable tumours derived from paraganglia, a diffuse neuroendocrine system dispersed from skull base to the pelvic floor. The carotid body, a small oxygen sensing organ located at the bifurcation of the carotid artery in the head and neck and the adrenal medulla in the abdomen, are the most common tumour sites. It now appears that mutations in SDHB, SDHC, and SDHD, which encode subunits of mitochondrial complex II (succinate dehydrogenase; succinate-ubiquinone oxidoreductase), are responsible for the majority of familial paragangliomas and also for a significant fraction of non-familial tumours. Germline mutations in complex II genes are associated with the development of paragangliomas in diverse anatomical locations, including phaeochromocytomas, a finding that has important implications for the clinical management of patients and genetic counselling of families. Consequently, patients with a paraganglioma tumour, including phaeochromocytoma, and a complex II germline mutation should be diagnosed with hereditary paraganglioma, regardless of family history, anatomical location, or multiplicity of tumours. This short review attempts to bring together relevant genetic data on paragangliomas with a particular emphasis on head and neck paragangliomas and phaeochromocytomas.

Chronic carotid glomitis and the glomus pulmonale.

A histological study was made of the carotid bodies and glomus pulmonale in 50 consecutive subjects over the age of 50 years who came to necropsy to determine if chronic glomitis is confined to the carotid bodies or whether it also occurs in other glomera. Lymphoid aggregates and plasma cell activity were found in the glomus pulmonale just as they were in the carotid bodies. Chronic pulmonary glomitis sometimes occurred in association with chronic carotid glomitis and sometimes independently of this. The mean age of the affected subjects was 76 years in isolated pulmonary glomitis and 79 years in chronic carotid glomitis. Chronic carotid glomitis affected seven (14%) subjects and predominated in women (six to one). In the seven cases of isolated pulmonary glomitis women predominated five to two. Chronic glomitis seems to be a disease process which may affect at least two members of the non-chromaffin paraganglionic system, but it is not clear why focal chronic inflammation affects the glomus pulmonale of one person but not of another.

Paraganglial cells of urinary bladder and prostate: potential diagnostic problem.

A transurethral prostatic resection for prostatism in a 73 year old man showed a cluster of richly capillarised clear cells originally thought to be indicative of invasive carcinoma. Immunohistochemical studies were carried out on this tissue specimen and three similar cases using a variety of antibodies--Neuron specific enolase, PGP 9.5, chromogranin, synaptophysin, serotonin, somatostatin, substance P, calcitonin, calcitonin gene related peptide, met-enkephalin, VIP, neurofilament, CAM 5.2, S100 protein, prostatic specific antigen and prostatic acid phosphatase. The cellular foci were shown to be composed of paraganglionic cells. The cell clusters were well defined and predominantly comprised clear cells with scanty, fine eosinophilic cytoplasmic granules in three cases. The cell nuclei were round to oval, moderately pleomorphic, with evenly dispersed dense chromatin. It is concluded that the presence of minute foci of paraganglial cells in the bladder wall and prostate gland may be misinterpreted as malignant because of their close association with nerves and their relative rarity. Immunohistochemical staining with neuroendocrine markers should dispel any doubt about their identity.

Immunohistochemistry of small intensely fluorescent (SIF) cells and of SIF cell-associated nerve fibers in the rat superior cervical ganglion.

Double-labelling immunofluorescence was applied on single sections of the rat superior cervical ganglion to evaluate neurochemistry and connectivity of intraganglionic SIF cells. The synaptic vesicle membrane protein synaptophysin and secretoneurin, a newly discovered neuropeptide derived from secretogranin II, proved reliable molecular markers of this cell type, whereas serotonin and tyrosine hydroxylase immunoreactivities were observed in slightly incongruent SIF cell subpopulations. Immunolabelling for vasoactive intestinal polypeptide and neuropeptide Y occurred in few SIF cells. None of the above immunoreactivities were visibly altered by preganglionic or postganglionic denervation, while some SIF cells were immunolabelled for galanin or for the neuronal microtubule-associated protein MAP2 after postganglionic denervation. SIF cells were nonreactive for the pan-neuronal marker protein gene product (PGP) 9.5 or neurofilament 160 kD. Intense staining of NADPH-diaphorase in some SIF cells, suggesting catalytic activity of nitric oxide synthase, could not be substantiated by immunoreactivity for this enzyme. SIF cells were approached by nonidentical fiber populations immunoreactive for PGP 9.5, neurofilament, or neuropeptide Y, whereas immunoreactivities for galanin and vasoactive intestinal polypeptide were colocalized in fiber meshes around SIF cells. The findings indicate (1) neurochemical SIF cell heterogeneity, (2) SIF cell plasticity in response to ganglionic perturbation, and (3) a differentiated innervation of SIF cells in the rat superior cervical ganglion.

Chemosensitivity, plasticity, and functional heterogeneity of paraganglionic cells in the rat coeliac-superior mesenteric complex.

Chemosensitivity and plasticity of paraganglionic cells in the rat coeliac-superior mesenteric complex (CSMC) were investigated at a basal state of normoxia (21% O2) and after long-term moderate hypoxia (10% O2, 14 days). Chemical sympathectomy previous to hypoxia was performed to destroy principal ganglionic neurons and thus to allow measurement of the norepinephrine and dopamine content of paraganglionic cells. At the basal state, the CSMC contained dopaminergic (TH+/DBH-) and noradrenergic (TH+/DBH+) paraganglionic cells, the majority being of the noradrenergic type. After 14 days of hypoxia, this ratio was reversed and dopaminergic cells predominated, as indicated by a twofold increase of TH+ cells and a twofold decrease of DBH+ cells. Biochemically, hypoxia produced an increase in the content (1.6-fold) and utilization (1.4-fold) of dopamine as well as a smaller increase in the content of norepinephrine, with no change in its utilization rate. The dopaminergic activation induced by hypoxia persisted after sympathectomy with guanethidine. It is concluded that paraganglionic cells in the CSMC display a chemosensitive function. Furthermore, our findings indicate that paraganglionic cells are differentially affected by hypoxia, depending on their distribution and the nature of their neuromodulators. The alterations induced by hypoxia point out the phenotypic plasticity developed by paraganglionic cells in adaptation to hypoxia and further demonstrate the functional heterogeneity of this autonomic cell population in the rat CSMC.

Denervation of peripheral chemoreceptors decreases breathing movements in fetal sheep.

The role of the peripheral chemoreceptors in the control of fetal breathing movements has not been fully defined. To determine whether denervation of the peripheral chemoreceptors affects fetal breathing movements, we studied 14 chronically catheterized fetal sheep from 120 to 138 days of gestation. In seven fetuses the chemoreceptors were denervated by bilateral section of the vagus and carotid sinus nerves; in seven others, sham operations were performed. We compared several variables during two study periods: 0-5 and 6-13 days after operation. In the denervated fetuses there were significant decreases in the incidence and amplitude of fetal breathing movements during both study periods. There were no differences between the two groups in incidence of low-voltage electrocortical activity, arterial pH and blood gas tensions, fetal heart rate, mean arterial blood pressure, or duration of survival after operation or birth weight. We conclude that denervation of the peripheral chemoreceptors decreases fetal breathing movements. These results indicate that the peripheral chemoreceptors are active during fetal life and participate in the control of fetal breathing movements.

Long-lasting hyperventilation induced by almitrine: evidence for a specific effect on carotid and thoracic chemoreceptors.

In anesthetized dogs, almitrine (0.5-3 mg/kg i.v.) induced a dose-dependent increase in respiratory rate and ventilation. The aortic and carotid chemoreceptors were involved in the effects of almitrine. Section of both carotid sinus nerves and vagus nerves abolished the effects of the drug on respiration. The respiratory response did not occur in dogs with bilateral lesions of the nucleus of the solitary tract. The electrical activity of chemoreceptor fibres was increased. Perfusion of almitrine into the carotid artery stimulated respiration. Inhalation of pure oxygen shifted the dose-response curve of the respiratory effect towards the right. Almitrine slightly stimulated ventilation in dogs with bilateral section of carotid sinus nerves and aortic nerves and this disappeared when both vagus nerves were cut indicating that this effect was mediated through some chemoreceptor fibres present in the vagus nerves or through afferent vagal fibres.

Laryngeal nerve paraganglia of the rat are morphologically and biochemically unchanged by long-term hypercapnia.

Exposure to hypercapnia (8.2 +/- 0.7% CO2) for 3 weeks failed to change the morphometric characteristics (mean cell area, nuclear, mitochondria and vesicle volume density) of the recurrent laryngeal nerve paraganglia of the rat. Moreover, this treatment had no effect on the dopamine and noradrenaline content of the superior and recurrent laryngeal nerves. The results are in contrast to what is found after exposure to hypoxia which increases the dopamine content and the cell area of the paraganglia and indicate that the mechanisms of the paraganglia in long-term hypoxia and hypercapnia differ.

Serotonin immunoreactivity in the autonomic intrapulmonary ganglia of the fetal sheep.

Using light microscopic immunohistochemistry, serotonin immunoreactivity was found in paraganglionic cells within pulmonary autonomic ganglia of fetal sheep at pseudoglandular and canalicular stages of lung development. Serotonin immunoreactive cells appeared individually or in clusters, and were occasionally seen around or in close contact with blood vessels.

Cholecystokinin-like immunoreactivity in cat extra-adrenal paraganglia.

In the cat peripheral dopaminergic organs such as the carotid body, subclavian bodies, aortico-pulmonary glomera and small intensively fluorescent cell (SIF cell) clusters of the superior cervical ganglion and the nodose ganglion were found to contain cholecystokinin (CCK)-immunoreactive paraganglionic cells. Thus, the extra-adrenal paraganglionic system may serve as a model for studying peripheral interactions of CCKergic and dopaminergic mechanisms.

Unusual eustachian tube mass: glomus tympanicum.

SUMMARY: A case of recurrent glomus tympanicum presenting with epistaxis is described. CT and MR imaging revealed a homogeneously enhancing mass extending along the entire course of the eustachian tube, with a portion protruding into the nasopharynx. Glomus tumors tend to spread along the path of least resistance and may extend into the eustachian tube. The unique imaging appearance should place a glomus tumor high on the list of differential diagnoses.

Beyond the promontory: the multifocal origin of glomus tympanicum tumors.

PURPOSE: We examined other middle ear locations of glomus tympanicum tumors, which arise from glomus bodies accompanying the tympanic (Jacobson's) nerve through the middle ear. Most descriptions place these tumors on the promontory over the basal turn of the cochlea. METHODS: We identified seven patients (all women) with small surgically confirmed glomus tympanicum tumors (not completely filling the middle ear) for whom CT scans were available for retrospective review. Patients' ages ranged from 23 to 78 years at the time of the high-resolution CT study (1.0- to 1.5-mm-thick sections). RESULTS: All tumors arose on the medial wall of the middle ear. One was anterior to the promontory, beneath the cochleariform process and the semicanal of the tensor tympani. Two were inferior to the promontory, in the recess beneath the basal turn of the cochlea. Four were anteroinferior. None was actually on the apex of the promontory. CONCLUSION: Glomus tympanicum tumors may arise in various locations on the medial wall of the middle ear, where Jacobson's nerve runs. The promontory is only one middle ear location in which glomus tympanicum tumors may arise. Familiarity with the course of the tympanic nerve helps tailor the search for, and facilitates accurate identification of, tiny glomus tympanicum tumors.

The neuroendocrine nature of the glomus cells: an experimental, ultrastructural, and histochemical tissue culture study.

Although the carotid body is an established chemoreceptor, there is considerable evidence also for its possessing a secretory function. While adrenergic neuroendocrine cells of neuroectodermal derviation exist in the central and autonomic nervous systems, the exact histogenesis of the mammalian carotid body is unsettled. The normal human carotid body and glomus jugulare tumor have been grown in tissue culture and their constituent cells have been observed to transform from epithelial to neuronoid appearing cells with extensive dendritic processes. This conversion has been further enhanced by the addition of nerve growth factor, a polypeptide specific for neural tissue. Electron microscopy confirmed that these culus cell. Histofluorescence revealed that these in vitro cells continued to synthesize and store biogenic monoamines in culture. Comparison of the morphologic, ultrastructural and histochemical features of the glomus cell with established neuroendocrine cells (central nervous system neurons, sympathetic ganglia cells, chromaffin cells) shows striking similarities. On the basis of these findings it is concluded that the glomus cell is a modified neuron of neural crest origin. The embryology, electron microscopy and histochemistry of the carotid body and related glomera and their tumors are reviewed.

Expression of angiogenic growth factors in paragangliomas.

OBJECTIVE/HYPOTHESIS: To determine if angiogenic growth factors including vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) are expressed in human paragangliomas. STUDY DESIGN: A histopathologic and molecular examination of paraganglioma specimens obtained from surgical cases or retrieved from the Pathology Department of the Massachusetts Eye and Ear Infirmary. METHODS: Fresh tumor or archival, paraffin-embedded paraganglioma specimens were analyzed by immunohistochemistry, Western blotting, and ELISA. RESULTS: Positive immunohistochemical staining for VEGF was observed in five of nine surgical specimens and in six of eight archival specimens (11/17, or 65%). PD-ECGF immunoreactivity was detected in four of five surgical specimens and six of eight archival specimens (10/13, or 77%). The presence of PD-ECGF was confirmed by Western blot assay and ELISA confirmed the presence of VEGF in tumor extract. CONCLUSIONS: Both VEGF and PD-ECGF are expressed in paragangliomas and may contribute to the extreme vascularity of these tumors. Key Words. Vascular endothelial growth factor, platelet-derived, endothelial cell growth factor, hypoxia, tumor vasculature.

Retrofacial approach to the hypotympanum.

Otologic disease often extends into the hypotympanum, posterior mesotympanum, and infralabyrinthine compartments. Surgical access to these areas can be difficult because of the proximity of the facial nerve. In patients with a normal bone anatomy, these regions can be accessed by a retrofacial approach, which spares the posterior canal wall and avoids transposition of the facial nerve. The anatomy of the hypotympanum, posterior mesotympanum, and infralabyrinthine compartments will be reviewed emphasizing gross anatomic documentation. We will detail the surgical approach to these areas along the retrofacial air cell tract, and will present an appropriate case history.

Computed tomography and magnetic resonance imaging of pathologic conditions of the middle ear.

Computed tomography (CT) is an excellent technique for demonstrating even small abnormalities of the thin and complex bony structures of the middle ear. For this reason, it is the modality of choice in the study of conductive hearing loss (CHL). However, not every patient complaining of CHL requires a CT study. In fact, established indications encompass complex conditions, such as the complications of acute and chronic otomastoiditis, the postoperative ear in chronic otomastoiditis or in the localization of prosthetic devices, and the assessment of congenital or vascular anomalies. Particularly, the precise extent of bone erosion associated with cholesteatoma is correctly demonstrated by high resolution CT. Conversely, although fistulization through the tegmen tympani or the posterior wall of temporal bone is usually detectable by CT, the actual involvement of meninges and veins are better assessed by magnetic resonance (MR). MR is also indicated when complicated inflammatory lesions are suspected to extend into the inner ear or towards the sigmoid sinus or jugular vein. Neoplasms arising from or extending into the middle ear require the use of both techniques as their combined data provide essential information. Most important data for surgical planning concern the destruction of thin bony structures and the relationships of the lesion with the dura and surrounding vessels. DSA and interventional vascular techniques maintain an essential role in the presurgical work-up and embolization of paragangliomas extended into the middle ear.

Growth factors and cytokines in paragangliomas and pheochromocytomas, with special reference to sustentacular cells.

The aim of this study was to localize various growth factors and cytokines in paragangliomas and pheochromocytomas in order to understand their possible autocrine or paracrine functions, and to compare sustentacular cells of the adrenal medulla with pituitary stellate cells. Thirteen resected tumors, 11 paragangliomas and 2 pheochromocytomas of the adrenal medulla, were studied. In addition, five surgically removed nontumorous adrenals and five nontumorous pituitaries were studied. Varying numbers of sustentacular cells were immunopositive for S-100 protein and in most instances for glial fibrillary acidic protein. Insulin-like growth factor-1 (IGF-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 were localized to both cell types in all cases, whereas epidermal growth factor (EGF) immunopositivity was noted in only three. In all tumors, leukemia inhibitory factor (LIF) was restricted to chief cells and EGF receptor to sustentacular cells. Nontumorous chief cells and sustentacular cells of adrenal medulla exhibited immunoreactivities similar to those of paragangliomas and pheochromocytomas. Secretory adenohypophysial cells displayed various immunoreactivities for all growth factors, receptors, and cytokines studied. Pituitary stellate cells were immunopositive for EGF, EGF receptor, IGF-1, LIF, and TNF-alpha. In conclusion, paragangliomas and pheochromocytomas are immunoreactive for a wide spectrum of growth factors and cytokines. Immunocytochemistry demonstrated similarities between sustentacular cells and stellate cells of the pituitary in addition to their similar morphology. The significance of these observations regarding paracrine activities of chief and sustentacular cells remains to be determined.

Ultrastructure of the gallbladder paraganglia.

The ultrastructure of the paraganglia in the gallbladder is identical to that of other nonchromaffin paraganglia featuring granule-bearing chief cells with many axons ensheathed by supporting cells. Synapses between axons, chief cells, and axons and chief cells are common. Ultrastructural similarities to the carotid body, proven to be a chemoreceptor, support a similar function for these paraganglia. An endocrine function is also suggested by the partial similarity of their structure to that of Zuckerkandl's organ.

Paraganglia in the human gallbladder.

Paraganglia found in the subserosa of nine of ten surgically removed gallbladders had morphologic features and staining characteristics similar to those of other sites. Although they were not difficult to locate in subserial sections, their sparseness and smallness explains the rarity with which they have been encountered in the routine histologic gallbladder examination. The strong, finely granular argyrophilia of the chief cell cytoplasm in all of the glomera studied offer a simple means of identifying them when only a portion of the structure is viewed.

Paraganglion of the prostate in a needle biopsy: a potential diagnostic pitfall.

Paraganglionic tissue incidentally observed in a needle biopsy of the prostate is reported. The tissue was seen in the periprostatic adipose tissue obtained during a needle biopsy of the prostate of an 81-year-old man. The paraganglionic cells demonstrated round to oval nuclei and basophilic granular or vacuolated cytoplasm and were immunohistochemically positive for chromogranin A, but negative for prostatic acid phosphatase and prostate-specific antigen. Paraganglion in the periprostatic adipose tissue is a diagnostic pitfall and should be distinguished from extension of prostatic adenocarcinoma outside the prostatic capsule into the periprostatic adipose tissue.