Biomedical subjects
Publications and source records attributed to M N Sheppard.
Histological examination of a lung removed at transplantation revealed multiple peripheral tumourlets and microcarcinoids in close association with bronchioles causing an obliterative bronchiolitis. This was an unexpected finding but explained the progressive airflow limitation which characterised the patient's clinical course.
BACKGROUND: Sclerosing mediastinitis is a rare condition which causes dense fibrosis of the mediastinum. Few large studies have been reported to date. The clinical and pathological features of cases have been studied in a specialist referral centre in the UK. METHODS: The pathological files of the Royal Brompton Hospital were examined and 18 cases of sclerosing mediastinitis were identified between 1970 and 1993. The clinical notes were obtained and the pathological specimens analysed. RESULTS: There were 12 men and six women of age range 9-64 years. Twelve patients presented with shortness of breath, six had haemoptysis, three had hoarseness, four had pleuritic chest pain, three general weakness, two had dysphagia, and one was asymptomatic. Nine patients had a previous history of pulmonary tuberculosis. Two had auto-immune disease--one rheumatoid arthritis and the other systemic lupus erythematosus. There were three cases of previous malignancy--two undifferentiated carcinoma of the lung and the other Hodgkin's disease. Serological tests revealed only one positive reaction to Histoplasma. The erythrocyte sedimentation rate and serum immunoglobulins were raised in nine patients. Diagnosis was usually by thoracotomy with biopsy. All cases had fibrosis and chronic inflammation with no active granulomas. No infective organisms or positive cultures were obtained in any case. Ten of the 18 cases are alive up to 15 years after diagnosis, with only two deaths and six lost to follow up. CONCLUSIONS: Sclerosing mediastinitis is a slowly progressive condition associated with previous tuberculosis, mediastinal malignancy, and autoimmune disease. The outlook is excellent for those cases without underlying malignancy.
OBJECTIVE: The endocardium contains an extensive neural plexus, the composition and function of which are unclear. The aim of this study was to characterise the innervation of the endocardium in terms of the relative density and distribution of its autonomic and sensory nerve subpopulations and to assess the relationship between these nerves and endocardial endothelial cells. METHODS: Immunohistochemical, histochemical, confocal, and quantitative image processing techniques were applied to whole mount preparations of human postmortem endocardium obtained within 24 h of death. RESULTS: The overall distribution of nerve fibres and fascicles was demonstrated using antisera to the general neural marker protein gene product 9.5 (PGP 9.5). Nerves displaying acetylcholinesterase activity represented the main nerve subpopulation, occupying 9-18% of the quantified field area. Neuropeptide Y immunoreactive nerves formed the most numerous peptide containing nerve subpopulation identified, occupying 5-19% and 2-7% of the field area in the ventricle and atrial endocardium respectively and having similar distribution patterns to tyrosine hydroxylase immunoreactive nerves. Nerves showing immunoreactivity for somatostatin, vasoactive intestinal polypeptide, and substance P were detected at a lower density, occurred more frequently in the ventricular than atrial endocardium, and showed a similar distribution in the right and left sides of the heart. Combined peptide immunofluorescence and acetylcholinesterase staining, of the same preparation, indicated that putative sympathetic and sensory nerve subpopulations could be distinguished from presumed parasympathetic, acetylcholinesterase positive, nerves. The relationship between immunostained nerves and endothelial cells was assessed using confocal microscopy. Varicose nerve fibres were detected within 0.2 micron of overlying endothelial cells in the right ventricle and between 0.4-0.6 micron in the left ventricle. CONCLUSIONS: The heterogeneous population of nerve fibres demonstrated in the human endocardium may influence the known interaction between endocardial endothelial cells and the myocardium.
Atypical carcinoids of the lung (well-differentiated neuroendocrine carcinomas) are rare tumours of uncertain prognosis. We have studied 33 cases--male to female ratio 2:1, age range 22-75 years, mean 55 years, 80% smokers, 15 peripheral and 18 central, tumour size 1.2-9.5 cm. Microscopically they had a nesting/insular, trabecular or lobular pattern. Nuclear morphology was variable, round cells, large cells and spindle cells being identified with small cell areas in five tumours. Mitotic activity varied from 4 to 80 per 1.52 mm2. Areas of necrosis were seen in all tumours. All 33 tumours were cytokeratin positive (AE1/AE3 and CAM5.2), 32 were positive for neuron-specific enolase, synaptophysin and chromogranin A. Electronmicroscopy showed dense core granules in 29 available cases. Nineteen cases were stage I, nine stage II, four stage III and one stage IV. Follow-up information was available for 22 cases. Size, location, stage and large cell/small cell morphology were important prognostic indicators. Large tumour size, large cell or mixed large cell/small cell morphology, peripheral localization and advanced stage were adverse prognostic indicators. Mitotic activity and the presence of necrosis did not appear to influence stage or behaviour.
Atypical carcinoids of the thymus are rare neoplasms of uncertain prognosis. We have studied eight cases (six male, two female; age range 48-60 years, mean 55 years), none with evidence of a paraneoplastic neuroendocrine syndrome. Tumour size was large and ranged from 7.5 to 10 cm. Microscopically, all had a nesting/insular or trabecular pattern, eosinophilic cytoplasm, round nuclei with fine chromatin and small nucleoli. No small cell features were evident. Mitotic activity ranged from 2 to 21 per 1.52 mm2. Focal necrosis was seen in all cases. All were positive for cytokeratin (AE1/AE3, CAM 5.2) and the neuroendocrine markers NSE, synaptophysin and chromogranin; five cases were positive for calcitonin. On electronmicroscopy all contained dense core granules, often numerous. Three cases were stage I and five stage III (infiltrating lung or chest wall). Follow-up information was available in four cases (one stage I and three stage III): the stage I tumour had local recurrence and metastasis to the lung within a year whilst the three patients with stage III tumours died of liver, bone and brain metastases within 3 years.
The case is described of a 36 year old woman who presented with a large left sided haemothorax. A thoracic computed tomographic (CT) scan suggested there was a bony outgrowth arising from the fourth rib. This was resected surgically and found to be an osteochondroma which was surrounded by blood clot. No definite site of bleeding was identified, but it is thought that the tumour may have traumatised the lung, the pericardiacophrenic artery, or the superior pulmonary vein, resulting in life threatening haemorrhage.
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BACKGROUND: Cardiac conduction is influenced by peptidergic mechanisms as well as classic neurotransmitters. The distribution of peptide-containing nerves has not been well defined. METHODS AND RESULTS: Immunofluorescence and histochemical techniques were used to visualize the innervation of the human conduction system and to distinguish nerve subpopulations according to their peptide and enzyme content. Nerve fibers and fascicles displaying immunoreactivity for protein gene product 9.5 (PGP 9.5) were more numerous in the sinus and atrioventricular nodes than in the penetrating bundle, bundle branches, and adjacent myocardium. The relative density of innervation was greater in the central region of the sinus node than in the peripheral regions. Nerve densities were also higher in the transitional region of the atrioventricular node compared with its compact region. Acetylcholinesterase (AChE)-positive nerves were the main subtype identified in the sinus and atrioventricular nodes, representing half to two thirds of the stained area occupied by PGP 9.5-immunoreactive nerves. Neuropeptide Y-immunoreactive nerves represented the main peptide-containing subpopulation and occurred throughout the conduction system, displaying a similar pattern of distribution and relative density to those demonstrating tyrosine hydroxylase immunoreactivity. Nerve fibers showing immunoreactivity for vasoactive intestinal polypeptide, somatostatin, substance P, or calcitonin gene-related peptide exhibited distinct patterns of distribution and comprised a relatively minor component of the innervation, the percentage of stained area being 10- to 40-fold lower than that occupied by neuropeptide Y- and PGP 9.5-immunoreactive nerves, respectively. CONCLUSIONS: The innervation of human conduction tissues exhibits significant regional variation and comprises putative parasympathetic nerves and intrinsic neurons (AChE positive), sympathetic efferent nerves (neuropeptide Y- and tyrosine hydroxylase-immunoreactive nerves), and other peptide-containing nerves, some of which (substance P and calcitonin gene-related peptide containing) are considered to represent afferent nerves. Locally released peptides may be involved in the neural modulation of the human conduction system.
The effects of vagal stimulation on pulmonary vascular permeability were studied in guinea pigs in vivo using 125I-labeled albumin as a marker of plasma extravasation. Bilateral vagus nerve stimulation (NS) significantly increased the plasma leakage index in both parenchyma and tracheobronchial tissues. The NS-induced plasma leakage in the parenchyma was unaffected by the alpha-adrenoceptor antagonist phentolamine, the muscarinic receptor antagonist atropine, the ganglionic blocker hexamethonium, or pretreatment with 6-hydroxydopamine or capsaicin, but it was significantly potentiated by the beta-adrenoceptor antagonist propranolol. NS-induced tracheobronchial vascular leakage was markedly inhibited by pretreatment with atropine, hexamethonium, or capsaicin, although it was unaffected by pretreatment with phentolamine, propranolol, or 6-hydroxydopamine. By itself, NG-nitro L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, had no effect on pulmonary vascular leakage, but it significantly enhanced the NS-induced plasma leakage to parenchyma in a dose-related and L-arginine-reversible manner. Elevation of blood pressure to a similar extent as that induced by L-NAME by a phenylephrine infusion had no significant effect on the increased plasma leakage induced by NS. These results suggest that vagal stimulation increases plasma extravasation in lung parenchyma through the release of unidentified transmitter(s) in a process that is modulated by endogenous NO and catecholamines (via activation of beta-adrenoceptors), and that different mechanisms are involved in the vagally induced plasma extravasation in the pulmonary and tracheobronchial vascular beds.
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The utility of computed tomography (CT) is well established in patients with chronic interstitial lung disease. There are currently no descriptions of the CT appearances of diffuse pulmonary haemorrhage. The CT findings of six patients with diffuse pulmonary haemorrhage are presented. Pathological correlation from open lung biopsies in two of these patients provided a pathological basis for the CT appearances. All six patients had diffuse nodular opacities with no zonal predominance. The nodules were of uniform size in any single patient but varied (1-3 mm diam.) between patients. Patchy areas of 'ground-glass' opacification of the lung parenchyma due to recent haemorrhage was associated with apparent prominence of the segmental bronchi and obscured the background nodularity. The CT findings were similar in all six patients and, although not pathognomonic, awareness of the CT features described should raise the possibility of the diagnosis.
Eleven cases of clinically diagnosed cryptogenic organizing pneumonia were examined in order to establish the histological features found at transbronchial biopsy and to correlate this with open lung biopsy which followed in six cases. The essential pathological feature was the presence of buds of granulation tissue (Masson bodies) indicating organization of a persistent exudate by fibroblasts and capillaries within alveoli, with preservation of the alveolar architecture. In addition, both acute and chronic inflammatory cells were present in the interstitium. These features, combined with the clinical history, were sufficient for a diagnosis in seven of the 11 cases on transbronchial biopsies. Four biopsies lacked these features. Patients proceeded to open lung biopsy in addition to the two with histological features of cryptogenic organizing pneumonia on transbronchial biopsy, but where the clinician wanted to eliminate other pathology because of rapid clinical deterioration. Five of the six cases coming to open lung biopsy confirmed cryptogenic organizing pneumonia with Masson bodies within alveoli, but changes were focal in three with very few Masson bodies in one. One case which had the features on transbronchial biopsy lacked them in the open lung biopsy. Transbronchial biopsy, therefore, can yield diagnostic material in the majority of patients with cryptogenic organizing pneumonia while open lung biopsy, which is considered the gold standard for interstitial lung disease, may yield negative results because of sampling error and the rapid evolution and changing pattern of the disease.
To establish if antibodies to alpha smooth muscle actin (ASMA) are better than desmin as a tumour marker in pulmonary lymphangioleiomyomatosis both antisera were applied to five cases. ASMA strongly stained the muscle in all cases but desmin was negative. Five cases of cryptogenic fibrosing alveolitis showed that mature smooth muscle embedded in fibrous tissue surrounding cysts was positively stained with ASMA but the interstitial fibrous tissue was negative. ASMA is a consistent and better marker than desmin for the detection of immature smooth muscle in pulmonary lymphangioleiomyomatosis.
The term cryptogenic organising pneumonia has been used for the combination of dyspnoea, cough, pleuritic pain, widespread shadows on chest radiographs, and histological evidence of intra-alveolar organisation with buds of granulation tissue within the alveoli. We report 12 patients with seasonal recurrence of this disorder for between 3 and 11 years. In all 12 patients, symptoms recurred between late February and early May every year, tending to increase in severity each year, and resolved between June and January. Chest radiography and computed tomography showed bilateral consolidation. Lung biopsy samples showed intra-alveolar buds of granulation tissue. There were many neutrophils within the lumina of medium-sized airways and terminal bronchioles showed evidence of obstruction by granulation tissue. Functionally, the predominant defect was restrictive and only 2 patients (life-long non-smokers) had airflow limitation. All 12 patients had very high activities of liver enzymes, suggesting intrahepatic cholestasis, but no other evidence of liver disease. Cultures of blood, sputum, lung tissue, and bronchoalveolar lavage fluid, viral screening, and complement fixation tests were consistently negative. In all patients all abnormalities responded rapidly to oral steroid therapy. These findings suggest a seasonal syndrome of organising pneumonia and biochemical abnormalities indicative of intrahepatic cholestasis. No aetiological factor has been identified, but the nature and periodicity of the illness point to an inhaled agent present in the environment for a limited period every year.
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We present a primary mucoepidermoid carcinoma of the thymus which is an extremely rare cause of mediastinal tumour. Growth is slow with cure obtained after complete resection. Only two previous cases have been reported.
A very large desmoid tumour extensively involving the chest wall and the left anterior abdominal wall is described in a patient with a family history of Gardner's syndrome. The desmoid arose at the site of a thoracotomy scar due to the removal of a large aneurysm of the left atrial appendage five years before. Both a plastic surgeon and a thoracic surgeon were required to remove the tumour. Aneurysmal dilatation of the left atrium is extremely rare and has not been reported in association with Gardner's syndrome before.
Solitary papillomas of the lung are rare. They are usually squamous but mixed squamous cell papilloma and mucous gland adenoma can occur. We report for the first time the cytological findings of a fine needle aspirate from a mixed squamous cell papilloma and mucous gland adenoma from the lung periphery.