M N Sheppard

Royal Brompton and Harefield NHS Foundation Trust, Harefield, England, United Kingdom

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Publications (75)350.88 Total impact

  • R Saluja · S Pomplun · T Eisen · M N Sheppard · A G Nicholson

    No preview · Article · Dec 2008 · Histopathology
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    ABSTRACT: Carcinoid tumours and small cell carcinomas of the lung share many characteristics with normal neuroendocrine cells. While carcinoid tumours contain many dense-cored neurosecretory granules and are frequently argyrophil, small cell carcinomas are poorly granulated and rarely argyrophil, which casts doubt on their neuroendocrine nature. Immunostaining of the enzyme neuron specific enolase (NSE) was recently used to demonstrate the neuroendocrine components of the lung including nerves and neuroendocrine cells. We therefore used NSE immunostaining to investigate neuroendocrine differentiation in 79 lung tumours, including 18 bronchial carcinoids and 31 small cell carcinomas, and compared these results with those obtained with silver stains. Thirteen of the 18 carcinoids were reactive to silver, all other types being negative. NSE-immunoreactivity occurred in 16 carcinoids and 18 small cell carcinomas. None of the squamous cell carcinomas, large cell anaplastic carcinomas and adenocarcinomas examined showed NSE-immucoreactivity. Radioimmunoassay of extractable NSE from 10 fresh lung tumours correlated well with the immunostaining results, demonstrating large amounts in two small cell carcinomas (334 and 517 ng/mg protein) and three carcinoids (152, 908, and 1143 ng/mg protein). Values were much lower for four squamous cell carcinomas (31–44 ng/mg protein) and one large cell anaplastic carcinoma (30 ng/mg protein) and were accounted for by the presence of NSE-positive nerves and neuroendocrine cells in the surrounding lung. NSE immunostaining is a useful marker of neuroendocrine differentiation in lung tumours and should prove particularly valuable in the diagnosis of small cell anaplastic tumours and their metastases.
    No preview · Article · Apr 2007 · Histopathology
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    ABSTRACT: We reviewed 45 pulmonary B-cell non-Hodgkin's lymphomas to determine whether their morphology and immunohistochemical features were those of lymphomas arising from mucosa-associated lymphoid tissue (MALT), as described in other sites. The polymerase chain reaction was used to provide further information on clonality. We found that these lymphomas infiltrate the pulmonary interstitium along bronchovascular bundles and interlobular septa, subsequently spilling out into airspaces and finally destroying the alveolar architecture of the lung. Central hyaline sclerosis and vascular infiltration were common features. All lymphomas stained CD20 positive and were accompanied by variable numbers of reactive CD3 positive T-cells. Cytokeratin staining with CAM 5.2 was useful in identifying lymphoepithelial lesions. CD21 staining of follicular dendritic cells revealed germinal centres where they were not recognizable on H & E staining. The polymerase chain reaction was performed on paraffin tissue from 28 patients. Twenty were low grade, of which 12 showed a clonal band and eight stiowed a polyclonal smear pattern. Eight were high grade, of which one revealed a clonal band. Three produced polyclonal smear patterns and four cases were inadequate samples. In one patient who had lymphoma at a second extranodal site, identical bands were identified, evidence for ‘homing’ of lymphoid cells towards mucosal epithelium.
    No preview · Article · Apr 2007 · Histopathology
  • A Fletcher · SY Ho · K P McCarthy · M N Sheppard
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    ABSTRACT: To quantify the variation in fibrosis, fat and muscle within the walls of both ventricles and within the different regions of the heart from six patients dying suddenly of arrhythmogenic right ventricular dysplasia (ARVD) aged 20-60 years. Seven heart regions were examined both macroscopically and histologically using the Picro-Sirius red stain. Quantification of fibrosis, fat and muscle was performed in each region and transmural layer using grid counting. There were macroscopic changes in all examined hearts. A higher percentage of fat with less fibrosis and muscle was observed within the right ventricle of the older patients. The left ventricle had more pathology in the older age group. Statistical differences in pathology in the heart were found. Fat predominated in the epicardial layer in the right and left ventricles of all patients, while the interventricular septum was the least affected. In ARVD, the pathology varies with age in both ventricles, fibrosis being the earliest hallmark of disease, with fatty infiltration evolving later. It should be labelled arrhythmogenic ventricular dysplasia because of biventricular involvement. Histopathologists should therefore sample from whole slices of the heart, so that all the changes can be observed.
    No preview · Article · Apr 2006 · Histopathology
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    ASM Fabre · M N Sheppard
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    ABSTRACT: To evaluate non-atherosclerotic cardiac deaths in the UK population aged over 15 years including elderly patients and to highlight the concept of the structurally normal heart in sudden death. Pathological data were collected prospectively for sudden adult deaths referred by UK coroners. 453 cases of sudden death from 1994 to 2003 (278 men (61.4%) and 175 women (38.6%), age range 15-81 years) were reviewed. Males predominated in both age groups (< or = 35 years, > 35 years). More than half of the hearts (n = 269, 59.3%) were structurally normal. In the other 40.7%, cardiac abnormalities were noted, which included: (1) cardiomyopathies (23%) such as idiopathic fibrosis, left ventricular hypertrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular dysplasia; (2) inflammatory disorders (8.6%) including lymphocytic myocarditis and cardiac sarcoidosis; (3) non-atheromatous abnormalities of coronary arteries (4.6%); (4) valve diseases; and (5) miscellaneous and rare causes. The concept of the structurally normal heart in sudden death and the need for histological examination to detect underlying disease is highlighted. Relatives need to be referred for cardiological and genetic screening in cases of normal hearts found at necropsy.
    Full-text · Article · Mar 2006 · Heart (British Cardiac Society)
  • M.N. Sheppard · A.G. Nicholson
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    ABSTRACT: Cystic fibrosis (CF) is one of the commonest lethal inherited conditions among Caucasians. It affects multiple organ systems and exhibits a range of clinical problems of varying severity. Life expectancy has improved in recent years as treatment regimes have become more intensive, but current treatments are expensive, often time consuming and may affect quality of life. New treatments for the pulmonary disease are under clinical trial and include antiproteases, amiloride, a sodium channel blocker, DNase and gene therapy. The gene for cystic fibrosis was identified in 1989 and this together with the emerging technology of gene therapy heralded a new dawn for the treatment of genetic disease. The lung is considered an ideal organ to target due to ease of access, but subsequent research has shown that the airway surface provides an efficient barrier to topically applied gene transfer agents. A number of Phase I clinical safety trials were carried out through the 1990s and provided proof of concept evidence that delivery of DNA by either viral or non-viral means was safe though not clinically efficacious. Current research is now focusing more on the barriers faced by delivery agents, with the aim that more efficient gene delivery will lead to a gene therapy for cystic fibrosis. The histopathologist is rarely called upon to make the initial diagnosis as cystic fibrosis is usually diagnosed clinically, being characterized by chronic bronchopulmonary infection, malabsorption due to pancreatic insufficiency and a high sweat-sodium concentration on sweat testing. Most information concerning both macroscopic and microscopic findings in cystic fibrosis has come from autopsy studies, so the pathological features are often extreme. However, with increasing survival of patients with cystic fibrosis, we are seeing more subtle changes in other organs and in addition, more aggressive drug therapy, gene therapy and lung transplantation are bringing with them new disease entities and complications.
    No preview · Article · Jan 2006 · Current Diagnostic Pathology
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    K Kontogianni · AG Nicholson · D Butcher · M N Sheppard
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    ABSTRACT: The diagnosis of small cell lung carcinoma (SCLC) on bronchial biopsy is often problematical as a result of intense crush artefact. Several antibodies are now available to help in the diagnosis of SCLC and their value was assessed in this clinical situation. Twenty cases of SCLC and 10 control cases (one non-Hodgkin lymphoma, three non-small cell carcinomas, one follicular reactive hyperplasia, and five chronic non-specific inflammations) with extensive crush artefact were stained using antibodies to CD56, MNF116, thyroid transcription factor 1 (TTF-1), and CD45. All SCLCs showed strong positive staining for CD56 in 75-100% of recognisable tumour cells, even in areas where there was extensive crush artefact. Eighteen of 20 cases were positive for TTF-1 and 16 of 20 were positive for MNF116 in the tumour cells, but both of these antibodies showed little or no staining in areas of crush artefact. Control cases comprising lymphoid cells were positive for CD45 in areas of crush artefact, but all cases of SCLC were negative. CD56, along with markers for cytokeratins-TTF-1, and CD45-are useful in the diagnosis of SCLC in biopsies with extensive crush artefact and can help confirm the diagnosis in cases where features are equivocal.
    Preview · Article · Oct 2005 · Journal of Clinical Pathology
  • D K Tansey · Z Aly · M N Sheppard
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    ABSTRACT: Fibrofatty replacement of the right ventricle wall, often with associated inflammation, is the hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare but established cause of sudden cardiac death in young adults. Fatty infiltration of the right ventricle alone without fibrosis may also occur but its relation to sudden death is not well established. In this study we assessed the amount of epicardial and intramyocardial fat in the right ventricle of 'normal' hearts from subjects who had died of non-cardiac causes. Hearts (n = 148) were examined from 81 males and 67 females, with an age range of 6 months to 68 years, who had died of non-cardiac causes. The extent and distribution of right ventricular epicardial and intramyocardial fat was assessed macro- and microscopically, respectively. The majority of hearts (85%) contained at least some intramyocardial fat with significantly more fat replacement noted in the right ventricles of older subjects and in females than in males. There was no significant fibrosis or inflammation in any of the 148 cases. Variable amounts of intramyocardial fat may be seen in the right ventricle of subjects dying of non-cardiac related causes. Care should be taken not to confuse this relatively common simple fatty infiltration with ARVC.
    No preview · Article · Feb 2005 · Histopathology
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    ABSTRACT: A 44-year-old woman presented with poorly controlled asthma and nodular radiological changes. A VATS lung biopsy confirmed talc granulomatous disease possibly related to her previous work as a dental technician. A detailed occupational history is mandatory. Talc granulomatous disease is one important alternative diagnosis in poorly controlled asthma.
    Full-text · Article · Dec 2004
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    A S John · R H Mohiaddin · M N Sheppard

    Preview · Article · Oct 2004 · Heart (British Cardiac Society)
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    Mary N Sheppard

    Preview · Article · Mar 2004 · BMJ (online)
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    R Ajitsaria · W I Awad · A Jaffe · M N Sheppard · P Goldstraw · D Hansell · A Bush
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    ABSTRACT: Case history An asymptomatic 8-week-old male infant was referred for assessment. A prenatal ultrasound had been suggestive of a congenital cystic adenomatoid malformation (CCAM). Fol- lowing delivery, he had a plain chest radiograph (fig. 1) and went on to have a computed tomography (CT) scan of the thorax (fig. 2), which showed an extrapulmonary mass close to the vertebral column. He proceeded to have magnetic resonance imaging of the thorax to look for intraspinal extension. The appearances were not anticipated, in that the lesion appeared to be intrapulmonary with no extension into the mediastinum, spinal canal or chest wall. The diaphragm was reported as being intact and separating the lesion from the abdominal cavity. There were no abnormal vessels reported. These features were in keeping with an intrapul- monary cystic lesion and the infant was referred for a surgical opinion. As the infant remained well, surgery was deferred until the child was 1-yr old. A routine pre-operative CT scan (fig. 3) was performed on the day before the planned surgery followed by a barium swallow (fig. 4). A surgical procedure for what
    Preview · Article · Mar 2004 · European Respiratory Journal
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    ABSTRACT: Cystic fibrohistiocytic tumour of the lung is a rare proliferative process. Its histogenesis is uncertain, but evidence suggests that some cases represent metastatic disease from apparently indolent skin lesions, namely cellular fibrous histiocytomas. This study presents four cases and reviews the literature concerning this pattern of disease and its aetiology. All patients were male (age range 35-54 years). Two presented with recurrent haemoptysis. Two cases had histories of cutaneous fibrohistiocytic lesions in the chest wall, excised 10 and 23 years prior to presentation with lung disease. Imaging data showed multiple bilateral cystic lung lesions in all four patients with nodular cavitating opacities seen on high-resolution computed tomography scans. Microscopy showed variably dilated thin-walled cystic airspaces lined by cuboidal epithelium and an underlying layer of mildly pleomorphic spindle cells with slightly wavy morphology and storiform architecture, admixed with inflammatory cells. Tumour cells stained for CD68 in three of four cases. All cases were negative for CD34. All patients were alive with disease, although one required pneumonectomy for intractable haemoptysis. This study and a review of published cases show that the majority of cystic fibrohistiocytic tumours of the lung probably represent metastases from cellular fibrous histiocytomas. However, rare cases may be either primary in origin or the primary site remains occult; the term cystic fibrohistiocytic tumour remains appropriate for such cases.
    No preview · Article · Jan 2004 · Histopathology
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    Sean C A Hughes · Mary Sheppard · Peter Goldstraw
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    ABSTRACT: A 33-year-old man underwent resection of a benign intramural schwannoma of the oesophagus. Similar clinicopathological and immunohistological features prompted a review of an earlier case initially diagnosed as a S-100 negative leiomyosarcoma. This stained positive using a new S-100 immunohistochemical antibody (Dako, Trappes, France). The frequency of these extremely rare tumours may be higher than initially thought. Pitfalls for the surgeon are highlighted and attention is brought to a recent consensus.
    Preview · Article · Jul 2003 · Interactive Cardiovascular and Thoracic Surgery
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    ABSTRACT: We report the case of a 52-year-old woman dying from a noninflammatory, occlusive vasculopathy. Histology showed marked intimal hyperplasia of small arteries of the intestines and myocardium with subsequent infarction of myocardium, large intestine and gallbladder. A comprehensive work up including laboratory studies, clinical investigations and postmortem failed to assign this condition to any of the known vascular diseases.
    No preview · Article · Jan 2003 · Cardiovascular Pathology
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    ABSTRACT: Sclerosing haemangiomas typically comprise a mixture of four architectural patterns (papillary, sclerotic, solid and haemorrhagic) and two cell types, eosinophilic cuboidal epithelial lining cells and sheets of rounded cells with either eosinophilic or clear cytoplasm. In most instances, recognition of these architectural and cytological features provides sufficient evidence for diagnosis. This study presents and discusses the histogenesis of four cases where difficulties in diagnosis were encountered, and reports the value of the antibody TTF-1 in making the diagnosis. Four cases with focal areas reminiscent of sclerosing haemangioma were reviewed and immunostained with an antibody panel including antibodies to TTF-1 and surfactant apoprotein A. Of these, one case was classified as sclerosing haemangioma combined with typical carcinoid, in which there was a mediastinal lymph node metastasis solely comprising the solid component of sclerosing haemangioma. The second was classified as an alveolar adenoma with sclerosing haemangioma-like areas. In the remaining two cases, diagnosis was confounded by presentation with predominantly cystic masses, the largest 70 mm in diameter. Immunohistochemically, TTF-1 was of greater value than surfactant apoprotein, in particular in identifying the solid component of sclerosing haemangioma when this was solely present. Sclerosing haemangiomas should be considered in the differential diagnosis of cystic pulmonary masses. They may also present histologically as combined tumours and metastasize to mediastinal nodes, indicating an, albeit low, malignant potential. TTF-1 is a valuable antibody in identifying the presence of a sclerosing haemangioma when typical features are absent.
    No preview · Article · Dec 2002 · Histopathology
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    ABSTRACT: Epithelial-myoepithelial carcinomas are very rare in the lung, and little is known about the relationship of their histologic features to prognosis. We describe five primary pulmonary epithelial-myoepithelial carcinomas with details on clinical presentation, histology, and immunohistochemical profiles. We also reviewed the literature to detail further their prognosis. The patients' ages ranged from 33 to 57 years (average 51 years). The tumors were all endobronchial and the patients presented with symptoms or imaging features of airway obstruction. The tumors were completely resected; none showed nodal involvement. All five patients are alive and free of disease 4 months to 8 years (average 4.2 years) after surgery. Four tumors showed a mixed pattern of glands lined by a dual layer of cells and solid sheets of either spindle cells or clear cells, the glandular and solid components being present in variable proportions. The fifth tumor comprised purely spindle cells. The mitotic rate was <1/20 high power fields in both the glandular and spindle/clear cell components. In one case there was focal nuclear pleomorphism. The inner layer of the glands stained for cytokeratins and epithelial membrane antigen, and the outer layer for S-100 and smooth muscle actin. In one case the spindle cells stained for CD34. A review of published cases shows the majority of tumors behave in an indolent fashion, the rare aggressive tumors being predominantly myoepitheliomatous. Nevertheless, the term epithelial-myoepithelial carcinoma is preferred because of their malignant potential. A high mitotic rate, tumoral necrosis, and nuclear pleomorphism appear to be adverse prognostic factors.
    No preview · Article · Dec 2001 · American Journal of Surgical Pathology
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    A.-G.A. Selim · L G Fulford · R H Mohiaddin · M N Sheppard
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    ABSTRACT: Relapsing polychondritis (RP) is a rare inflammatory multiorgan disorder affecting cartilaginous structures and other connective tissues. Serious cardiovascular complications have been reported in patients with RP, the most frequent being aortic or mitral regurgitation and aortic aneurysms. Aortitis is a very rare complication. An unusual case of active aortitis in a patient with RP, despite intensive immunosuppressive treatment, is described with a special emphasis on the pathological findings.
    Preview · Article · Dec 2001 · Journal of Clinical Pathology
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    ABSTRACT: Anastomosis of the ascending aorta to the right pulmonary artery, the so-called Waterston shunt, was undertaken as a palliative procedure for children with cyanotic congenital heart disease due to obstruction of the pulmonary outflow tract with reduced pulmonary blood flow. We present the clinicopathological correlations in two patients who underwent construction of Waterston shunts as neonates, and subsequently died of ruptured pulmonary aneurysms in adult life. Rupture should, therefore, be recognized as a late complication of this procedure, and be considered in the long-term follow-up of such patients, especially when the shunted lung is hypertensive.
    No preview · Article · Feb 2001 · Cardiology in the Young
  • M.N. Sheppard
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    ABSTRACT: Hypertrophic cardiomyopathy is a complex genetic and phenotypic disease. It is far commoner than originally thought, with an incidence of 1/500 of the population, making it one of the most common genetic diseases that pathologists may come across, particularly in their coroner's practice. It is regarded as the commonest cause of sudden cardiac death in those under the age of 35. From the pathologist's point of view it is important to make the diagnosis since it has important implications for the family regarding screening and prevention of sudden death. Pathologists need to be aware of the variable findings at autopsy depending on age, mutation type, hypertension, ischaemic damage, outlet obstruction etc. Histological examination with multiple sampling of the left ventricle is essential since myocyte disarray is the histological cornerstone of diagnosis.
    No preview · Article · Dec 2000 · Current Diagnostic Pathology

Publication Stats

3k Citations
350.88 Total Impact Points


  • 1995-2006
    • Royal Brompton and Harefield NHS Foundation Trust
      • • Department of Paediatrics
      • • Respiratory Medicine
      Harefield, England, United Kingdom
  • 1990-2000
    • National Heart, Lung, and Blood Institute
      베서스다, Maryland, United States
  • 1996
    • Imperial College London
      Londinium, England, United Kingdom
  • 1991-1996
    • The Heart Lung Center
      Londinium, England, United Kingdom
  • 1986
    • University College London
      • Department of Pathology
      London, ENG, United Kingdom
  • 1982-1984
    • Ealing, Hammersmith & West London College
      Londinium, England, United Kingdom