The carotid bodies in bronchial asthma

A histological study was made of right-sided carotid bodies resected therapeutically from 50 patients with bronchial asthma. Also studied as controls were 10 right-sided carotid bodies from subjects coming to necropsy. Hypoxaemia was considered a contra-indication to glomectomy and only patients with a resting arterial oxygen tension exceeding 65 mm Hg were submitted to operation. It was found that in patients with a short history of bronchial asthma the carotid bodies were not enlarged, but there was hyperplasia of sustentacular cells. In cases with asthma for 5 years or more the sustentacular cell hyperplasia was more pronounced and was associated with many nerve fibrils and slight enlargement of the carotid bodies. The functional significance of the proliferation of sustentacular cells and the abundance of nerve axons is obscure. In the asthma cases there was prominence of the dark variant of chief cells, thought to be related to episodes of hypoxaemia.     

Histopathology of the carotid bodies in neonates and infants

A histological study was made of the carotid bodies obtained at necropsy in 40 fetuses, neonates, infants and young children, ranging in age from 23 weeks of gestation to 11 years of age. Prominence of the dark variant of chief cells was found in diseases such as bronchiolitis which are associated with sustained hypoxaemia. Such cells have copious cytoplasm known to be rich in peptides such as enkephalins. The same histological features were found in two cases clinically diagnosed as sudden infant death syndrome but in which there was associated bronchiolitis and tracheo-bronchitis respectively, thought to have given rise to hypoxaemia. In a case of sudden infant death syndrome without infection there was overgrowth of sustentacular cells with predominant progenitor cells in the absence of dark cells. We associate this appearance with inability of the carotid bodies to respond adequately to changes in arterial oxygen tension.     

Comparative pathology of the enlarged carotid body

A histological study was made of the carotid bodies of man and various animal species from low and high altitudes. The animals studied were the alpaca, llama, cattle, guinea-pig, rabbit, dog, rat and man. As well as a qualitative microscopic study, a differential cell count was carried out to determine the percentage of the light and dark variants of chief cells and of sustentacular cells present. The investigation showed that the carotid bodies enlarge in cattle, guinea-pigs and rabbits living in the hypobaric hypoxia of high altitude to which they have to acclimatize. The carotid bodies are not enlarged in llamas and alpacas which show Darwinian adaptation to high altitude. There is no single histopathological appearance to be found with enlargement of the carotid body; on the contrary, there appears to be a characteristic histological reaction for different species. Thus, man shows hyperplasia of sustentacular cells, cattle show focal dark cell proliferation and rabbits, guinea-pigs, and dogs show striking hyperplasia and vacuolation of chief cells. In the rat, the enlargement of the carotid body is not characterized by the differential proliferation of any specific element and, as a result, it does not appear to be a good model for the human organ. In man and rat, carotid body enlargement occurs in response to systemic hypertension as well as to chronic hypoxaemia and the histological response to the 2 stimuli is the same, depending on the species. The normal rabbit carotid body is more reminiscent of that of man but, in this species, the reaction of glomic tissue differs from that of human glomic tissue.     

Multiparameter DNA flow-sorting demonstrates diploidy and SDHD wild-type gene retention in the sustentacular cell compartment of head and neck paragangliomas: chief cells are the only neoplastic component

Head and neck paragangliomas are considered to be biphasic tumours, composed of two distinct cell types: chief cells and sustentacular cells. A substantial number of these tumours show mutations in the SDHD gene located at chromosome 11q23. Although there is general agreement that paragangliomas are a neoplastic proliferation of chief cells, the nature of sustentacular cells is still a matter of debate. To clarify the nature of sustentacular cells further, multiparameter DNA flow cytometry was performed utilizing S-100 labelling as a selective marker of the sustentacular fraction simultaneously with DNA content measurement in six head and neck paragangliomas. S-100-positive fractions and other tumour-cell populations were flow-sorted and restriction digestion analysis of SDHD mutations was performed on each fraction. Flow cytometry demonstrated that the S-100 labelled cells were diploid. Restriction digestion analysis in informative cases revealed retention of the wild-type SDHD allele in S-100-positive fractions and loss of the wild-type allele in S-100-negative fractions. These data strongly suggest that sustentacular cells should be regarded as a non-neoplastic cell population that may be induced as a tumour-specific stromal component by chief cells.     

Enlargement of the carotid bodies in cirrhosis of the liver

The carotid bodies were dissected out at necropsy and weighed in seven subjects with cirrhosis of the liver and in seven control subjects of comparable age free of liver disease. The mean combined carotid body weight of the control group was 17mg but in the cirrhotic patients it was 35 mg, a statistically significant difference ( P < 0.005). Differential counts of the various types of glomic cell (progenitor, dark and light variants of chief cells and sustentacular cells) were carried out. The enlargement of the carotid bodies in the subjects with cirrhosis was associated with increased numbers of the dark variant of chief cell. The mean number of dark cells per unit area in the control group was 361 cells/mm² but in the cirrhosis group it was 1024 cells/mm², a statistically significant difference ( P < 0.005). It is postulated that the prominence of dark cells may be associated with secretion of a natriuretic peptide in response to the hyperaldosteronism and sodium retention of cirrhosis of the liver. Alternatively, it may be a response to hypoxaemia resulting from porta-pulmonary shunts.     

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-α (TNF-α), 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-α. 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.     

Mast cells in the human carotid body.

Mast cell counts were carried out on sections of human carotid bodies from 39 subjects showing one of four stages of histological change associated with aging, and in five subjects showing different forms of histopathology in the carotid body associated with disease. There was no relation between mast cell density and age or the histological changes associated with aging of glomic tissue. The normal range of mast cell density calculated in terms of the 80% confidence limits was 18.5 to 67.5/mm2. In three middle aged subjects with carotid bodies of normal histological appearance there was an abnormally high density of 83 to 96/mm2. In two elderly subjects showing age changes of fibrosis and accumulation of lymphocytes there was an abnormally low density of 12/mm2 or less. Mast cell density was not related to different types of carotid body hyperplasia. The mast cells were essentially stromal in location, usually closely applied to the walls of small glomic blood vessels, and were rarely found in intimate association with glomic chief cells. This suggests that mast cells are not directly concerned with the functions of glomic cells but does not preclude the possibility that they may have some effect on regulating glomic blood vessels and thus participate in the distribution of blood supply within the carotid body.     

The distribution of enkephalins in human carotid bodies showing cellular proliferation and chronic glomitis

Human carotid bodies obtained at necropsy that showed prominence of either the sustentacular cell or the dark variant of chief cell or chronic carotid glomitis were studied by an immunogold labeling technique. The peptides methionine and leucine enkephalin had a similar distribution to that found in the normal human carotid body. They were localized prominently and predominantly in the dark and progenitor variants of chief (type I) cells. The sustentacular (type II) cells showed no immunoreactivity for the enkephalins. Cell counts on immunolabeled chief cells in cases of sustentacular cell hyperplasia and chronic carotid glomitis were found to be at the lower end of the normal range, whereas those in dark cell prominence occurred nearer the upper limit.     

Fine structure of the rat carotid body transplanted into the anterior chamber of the eye

Summary Rat carotid bodies transplanted into the anterior chamber of the eye were studied by electron microscopy. Chief and sustentacular cells and a few ganglion cells survived for 3 months and maintained cytological characteristics similar to those in the intact carotid body. The transplant contained many fenestrated capillaries. Chief cells at the periphery of the cell cluster had long cytoplasmic processes which projected into the stroma of the iris. The cell processes became incorporated into bundles containing nerve fibres, which were enveloped by a perineurial sheath. Three types of nerve fibres were identified in the explant. Type I and type II nerve fibres (presumptive cholinergic and adrenergic, respectively) were enclosed by sustentacular and satellite cells. Most of the nerve fibres were completely separated from chief cells and ganglion cells by sustentacular and satellite cells. A few nerve fibres made direct apposition to chief cells and ganglion cells, where some nerves were presynaptic to them. Type III nerve fibres derived from myelinated nerve fibres were also enclosed by sustentacular and satellite cells.     

Multicentric metachronous pulmonary and intravagal paraganglioma: a case report with immunohistochemical findings

An unprecedented presentation of multicentric paraganglioma in a 48-year-old man is described. One of the paragangliomas, originally diagnosed as a carcinoid tumor, presented as a lung mass and was removed. Four years later, an intravagal paraganglioma was discovered. The lung and intravagal tumors had identical morphologic and immunoreactive characteristics. Both tumors consisted of chief cells (type 1) and sustentacular cells (type 2). The chief cells were immunoreactive with neuroendocrine markers (synaptophysin and chromogranin), but nonreactive with epithelial markers (CAM 5.2, high- and low-molecular-weight keratins, epithelial membrane antigen, and carcinoembryonic antigen). The sustentacular cells were positive for S100 protein. Although pulmonary carcinoids may mimic paragangliomas and occasionally contain sustentacular cells, the diagnosis was rejected because the tumor cells did not demonstrate reactivity with epithelial markers.     

Dark cell proliferation in carotid body hyperplasia

The histopathology of the enlarged carotid bodies, in both qualitative and quantitative terms, is described in two cases. One was in a woman of 80 years with systemic hypertension and the other in a man of 72 years with pan-acinar emphysema complicated by chronic hypoxaemia. In both instances there was generalized hyperplasia of sustentacular cells, perhaps with involvement of Schwann cells and fibrocytes, with superimposed focal proliferation of dark or 'pyknotic' variants of chief cells. The functional significance of both froms of tissue response in the carotid bodies is speculated upon.     

Carotid body tumor mimicking adenocarcinoma on fine-needle aspiration

We report an 86-year-old woman who presented with a 6-month history of a mass in the left side of her neck. MRI and MRI angiography favored a diagnosis of a neural tumor. FNAB showed a large cluster of cohesive, pleomorphic cells with intranuclear inclusion bodies; a diagnosis of adenocarcinoma was favored. At surgery, a 7 x 5 x 2.5 cm, firm, encapsulated mass was excised. Microscopically, the richly vascularized tumor had characteristics of a CBT, with large pleomorphic chief cells and spindle-shaped sustentacular cells in small, poorly formed nests. The chief cells were strongly immunoreactive for neuron-specific enolase and chromogranin, and focally positive for neurofilament, enkephalin, somatostatin, and beta-endorphin. The sustentacular cells were strongly immunoreactive for S-100 protein and glial fibrillary acidic protein and focally positive for vimentin. Ultrastructurally, the chief cells contained abundant neurosecretory granules. We emphasize that CBT must be included in the differential diagnosis of lateral neck masses. The distinction from adenocarcinoma is difficult on FNAB. The marked cytological atypia in an aspirate of a CBT does not indicate malignancy and may lead to an erroneous diagnosis.     

慢性低氧时牦牛和迁饲黄牛颈动脉体组织形态的比较

目的对牦牛、迁饲黄牛及低海拔黄牛颈动脉体(CB)形态及CB中低氧相关因子的表达进行比较,探讨高原土生或迁饲动物CB适应慢性低氧的模式。方法采集青海地区海拔3000~4000m的9头牦牛、2500m的9头高山迁饲黄牛及甘肃平原海拔1300米的12头低海拔黄牛的CB,固定、切片、染色后行光学显微镜和电子显微镜比较观察,并对CB中低氧诱导因子-1α(HIF-1α)、一氧化氮合酶(NOS)、瘦素受体(LEPR)、促红细胞生成素(EPO)等低氧相关因子的表达进行免疫组织化学观察。结果相比黄牛,牦牛CB体积较小,不同海拔牦牛的CB大小、形态及主细胞数量差异无显著性,而迁饲黄牛CB体积较低海拔黄牛大。牦牛CB主细胞中明细胞、暗细胞和固缩细胞的数量百分比比例为67.1%∶28.2%∶4.7%,迁饲黄牛为78.5%∶18.6%∶2.9%,低海拔黄牛为87.3%∶10.2%∶2.5%;与低海拔黄牛相似,牦牛CB少部分明细胞胞质透亮,暗细胞胞核染色质较致密并呈粗颗粒状,而迁饲黄牛CB大部分明细胞胞质透亮,暗细胞胞核染色质致密,颗粒稀少。3种牛支持细胞形态差异无显著性。与低海拔黄牛相比,迁饲黄牛CB主细胞的少数核异染色质增多,个别形态异常,胞质内多数细胞器肿胀溶解,残留少量细胞器和致密核心囊泡。3种牛CB中均有不同程度的HIF-1a、NOS、LEPR、EPO的蛋白表达,其中牦牛CB中EPO蛋白表达阳性率较低海拔黄牛明显降低(P0.05)。结论海拔高度不是影响牦牛颈动脉体大小和主细胞数量的主要因素。迁饲黄牛CB主细胞中细胞类型的比例与牦牛有趋同性改变,但缺氧时行使功能的I型细胞功能系统受损,尚处于低氧环境下的习服阶段。慢性低氧可能主要影响牦牛和迁饲黄牛CB中EPO蛋白表达。     

Bilateral carotid body tumor: the role of fine-needle aspiration biopsy in the preoperative diagnosis

Carotid body (CB) is a round to ovoid or flattened structure situated within the adventitia of the common carotid artery bifurcation on both sides of the neck. CB contains two basic types of cells: chief cells (or glomus type 1) and sustentacular cells (glomus type 2). Carotid body tumor (CBT) or paraganglioma arises from the chief cells of the carotid body. The diagnosis of CBT is typically made with radiological studies. Fine needle aspiration biopsy (FNAB) is seldom requested for this purpose due to rare but dreadful reported complications such as hemorrhage and damage to the carotid artery. In this report we discuss the cytological findings of a malignant CBT diagnosed by FNAB in a 22 year-old female.     

Paragangliomas of the head and neck: immunohistochemical neuroendocrine and intermediate filament typing

Twenty-nine paragangliomas of the head and neck region including 20 glomus jugulare (GJ) and nine carotid body (CB) tumors were evaluated for the presence of neuroendocrine and intermediate filament antigens. Immunohistochemistry on formalin-fixed, paraffin-embedded tissue was used to identify: S-100 protein (S-100); neuron-specific enolase (NSE); chromogranin A (CHA); serotonin (SER); synaptophysin (SYN); cytokeratin (CK); neurofilament (NF); desmin (DES); vimentin (VIM); and glial fibrillary acidic protein (GFAP). S-100 protein staining of sustentacular cell nuclei and cytoplasm was found in all tumors and was present in chief cells in 4 of 20 GJ and 3 of 9 CB tumors. All tumors stained with at least three neuroendocrine markers (29 of 29 NSE, 28 of 29 SYN, 26 of 29 CHA, 25 of 29 SER). CK was detected in 2 GJ and 1 CB tumor using anticytokeratins AE 1/3 and CAM 5.2. Neurofilament protein could not be demonstrated in fixed material, and all tumors were negative for GFAP and desmin. Vimentin was inconsistently detected in chief and sustentacular cells. We conclude that, in formalin-fixed material, paragangliomas have S-100 protein staining of sustentacular cells with chief cells containing antigens associated with neuroendocrine differentiation. The presence of CK in some paragangliomas is consistent with recent tissue culture studies demonstrating immunoblot confirmation of CK in pheochromocytomas and represents a potential source of immunohistologic misinterpretation in diagnosis, unless a panel of markers is utilized.     

Paragangliomas: assessment of prognosis by histologic, immunohistochemical, and ultrastructural techniques

To predict clinical outcome, we studied 42 paragangliomas from 37 patients by routine histology, immunohistochemistry, and electron microscopy. A panel of antisera to neuron-specific enolase (NSE), chromogranin, and met-enkephalin was used to identify chief (type I) cells, and S-100 protein and glial fibrillary acid protein (GFAP) sustentacular (type II) cells. The intensity of staining of type I cells and the density of type II cells were assessed semiquantitatively (0 to 4+) in a total of 38 tumors. A total of 23 of 24 low-grade tumors (solitary, multiple, or associated with other neoplasms; 95.8%) contained type II cells immunoreactive with either S-100 protein or GFAP, and all were positive when S-100 protein and GFAP were used in combination. Five of the nine intermediate-grade (recurrent and/or locally aggressive) tumors were identified as glomus jugulare tumors (GJT). Three intermediate-grade GJTs were devoid of GFAP-reactive type II cells and four GJTs were negative for S-100 protein. Type II cells were identified in only one of five high-grade (malignant) paragangliomas and that tumor contained vanishingly rare cells that were weakly S-100 protein positive but GFAP negative. Sustentacular cell density and chief cell staining intensity were both inversely related to tumor grade. The most sensitive chief cell marker was NSE (92.1%), followed by chromogranin (84.2%). The least sensitive (73.0%) and specific marker was met-enkephalin. Combinations of NSE or chromogranin with met-enkephalin identified chief cells in all cases. Electron microscopy identified neurosecretory granule-containing chief cells, but was of less value in delineating sustentacular cells because of their scarcity and the absence of specific features. By comparison, immunohistochemistry was superior in identifying sustentacular cells. The use of an immunohistochemical panel, in addition to routine histology, can confirm the diagnosis of a paraganglioma and can give an indication of the likely prognosis for a patient.     

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.     

Hyperplasia of the carotid body

The histopathology of hyperplasia of the carotid bodies was studied in 6 cases of hypoxaemia and right ventricular hypertrophy secondary to pan-acinar emphysema, and in five cases of systemic hypertension with left ventricular hypertrophy. The features of the hyperplasia were the same in the two groups. There was proliferation of sustentacular (type II) cells and compression of central cores of chief (type I) cells. It is speculated that the hyperplasia of sustentacular cells is associated in some way with the prevention of retention of sodium ions and water which characterises hypoxic cor pulmonale in "blue bloaters", systemic hypertension, and ascent to high altitude with the complications of acute mountain sickness, and pulmonary and cerebral oedema.     

The carotid bodies in a case of ventricular septal defect

A woman of 62 years with Turner's syndrome died in congestive cardiac failure secondary to a large ventricular septal defect with biventricular hypertrophy. During her last few months the lifelong left-to-right shunt underwent reversal exposing her carotid bodies to hypoxaemia. The carotid bodies were not enlarged, thus demonstrating that hyperplasia of glomic tissue is not brought about by increased myocardial mass per se. They were, however, abnormally cellular with more dark cells ( a variant of chief cells), many of which were abnormally large and showed ultrastructural features of metabolic activity. These changes may represent the earliest histological response of the carotid body to hypoxaemia and later, the dark cells may mature into the more familiar and common light variant. It seems likely that this dark cell activity precedes, probably by a long period, the sustentacular cell hyperplasia and proliferation of nerve axons which we have reported elsewhere as the chronic reaction of the carotid bodies to hypoxaemia.     

Sox10-positive sustentacular cells in neuroendocrine carcinoma of the lung

Tsuta K, Raso M G, Kalhor N, Liu D C, Wistuba I I & Moran C A
(2011) Histopathology  58, 276–285
Sox10‐positive sustentacular cells in neuroendocrine carcinoma of the lung Aims: Sustentacular cells are found in approximately half of pulmonary carcinoid tumours. However, most studies of sustentacular cells have used the less‐specific antibody to the S100 protein, and any correlation between the presence of sustentacular cells and other clinicopathological factors is unclear. The aim of this study was to analyse the significance of sustentacular cells in pulmonary neuroendocrine carcinomas (NECs). Methods and results: A Sox10 antibody was used to investigate 113 pulmonary NECs. Sustentacular cells were observed in 66.7% of typical carcinoid (TC) and 58.3% of atypical carcinoid (AC) cases, but not in high‐grade NECs. Sustentacular‐rich tumours had a statistically significant correlation with peripheral locations. We found no statistical differences in age, gender, smoking history, overall survival, or the occurrence of lymph node metastasis. In all but one case, when sustentacular cells were present in the primary site, they were also present in the metastatic lymph nodes. The presence of sustentacular cells differed in morphological subtypes, with the spindle pattern being the most common subtype. Conclusions: Sox10‐positive sustentacular cells were observed in carcinoid tumours but not in high‐grade NECs. Sustentacular‐rich carcinoid tumours did not show a correlation with the occurrence of lymph node metastasis or survival. The sustentacular cells found differed in morphological subtypes.