Improving standards in flexible bronchoscopy for lung cancer.

Can the detection rate of flexible bronchoscopy for lung cancer be increased by a series of simple quality improvement measures? Bronchoscopy-associated clinical parameters were prospectively recorded between 2001 and 2007 in patients with suspected lung malignancy. The detection rate of bronchoscopy, diagnostic yield of each biopsy modality and the possible impact of different service-improvement measures were assessed. 746 bronchoscopies were performed in 704 patients. The detection rate of bronchoscopy for malignancy was 83.6%, and increased over time (67.3% detection rate in 2001 (95% CI 52.9-79.7), 89.7% detection rate in 2007 (95% CI 81.3-95.2); p<0.001). Detection rate increased for bronchoscopically visible (75.0% in 2001 to 94.5% in 2007) and non-visible tumours (41.7% in 2001 to 81.2% in 2007; p<0.001 for both analyses). Prior computed tomography availability was associated with a higher diagnostic yield that did not reach statistical significance. Logistic regression analysis identified tumour visibility, year of study, use of transbronchial needle aspiration and pathologist identity as independent predictors of a positive diagnosis. A significant increase in bronchoscopic detection rate for malignancy occurred in association with a number of simple improvement measures.

Inter-observer variation between pathologists in diffuse parenchymal lung disease.

BACKGROUND: There have been few inter-observer studies of diffuse parenchymal lung disease (DPLD), but the recent ATS/ERS consensus classification provides a basis for such a study. METHODS: A method for categorising numerically the percentage likelihood of these differential diagnoses was developed, and the diagnostic confidence of pathologists using this classification and the reproducibility of their diagnoses were assessed. RESULTS: The overall kappa coefficient of agreement for the first choice diagnosis was 0.38 (n = 133 biopsies), increasing to 0.43 for patients (n = 83) with multiple biopsies. Weighted kappa coefficients of agreement, quantifying the level of probability of individual diagnoses, were moderate to good (mean 0.58, range 0.40-0.75). However, in 18% of biopsy specimens the diagnosis was given with low confidence. Over 50% of inter-observer variation related to the diagnosis of non-specific interstitial pneumonia and, in particular, its distinction from usual interstitial pneumonia. CONCLUSION: These results show that the ATS/ERS classification can be applied reproducibly by pathologists who evaluate DPLD routinely, and support the practice of taking multiple biopsy specimens.

Reduced expression of cyclooxygenase (COX) in idiopathic pulmonary fibrosis and sarcoidosis.

AIMS: To test the hypothesis that cyclooxygenase (COX)-1 or COX-2 expression is defective in lungs in idiopathic pulmonary fibrosis (IPF) and to characterize the cellular distribution. IPF is a progressive inflammatory lung disorder with an adverse prognosis. Previous work has shown that prostaglandin E2 (PGE2) regulates collagen deposition and fibroblast proliferation and a defect in COX regulation may contribute to the fibrosis that occurs in IPF. METHODS: Immunohistochemistry was utilized to determine COX immunoreactivity in lung sections from 25 IPF, six sarcoidosis and 14 control subjects. RESULTS: COX-1 and COX-2 expression in bronchiolar epithelial cells was significantly lower in IPF and sarcoidosis than in controls. No significant difference was found in COX-2 expression between macrophages in IPF and control sections, but COX-2 was reduced in macrophages in sarcoidosis compared with controls. CONCLUSIONS: These studies confirm COX-2 loss in bronchial epithelial cells but not macrophages in IPF, and show for the first time reduced constitutive COX-1 expression in epithelial cells and macrophages. Similar abnormalities were observed in sarcoidosis.

The TSC-2 product tuberin is expressed in lymphangioleiomyomatosis and angiomyolipoma.

AIMS: Lymphangioleiomyomatosis is categorized by proliferation of abnormal smooth muscle cells (LAM cells) in the lungs and lymphatics and the presence of angiomyolipomas. Recently mutations in the tuberous sclerosis complex-2 gene (TSC-2) have been described in LAM cells and angiomyolipomas. The TSC-2 protein tuberin is a tumour suppressor and its loss may result in cellular proliferation. We used immunohistochemistry to test the hypothesis that uncontrolled cellular proliferation in lymphangioleiomyomatosis is the result of reduced tuberin protein expression. METHODS AND RESULTS: Tissue from normal lung, normal kidney, lymphangioleiomyomatosis and angiomyolipomas was immunostained with three separate anti-tuberin antibodies. Tuberin staining in normal tissues was similar to that previously described. Surprisingly, tuberin was strongly expressed in the LAM cells of all cases of lymphangioleiomyomatosis and angiomyolipoma at a greater level than in normal smooth muscle cells. The perivascular cells of angiomyolipomas, however, did not stain for tuberin. CONCLUSIONS: Our results suggest that a loss of tuberin protein in LAM cells is not the cause of the cellular proliferation seen in lymphangioleiomyomatosis. Lymphangioleiomyomatosis may result either from the expression of a mutant tuberin with abnormal function, as a result of mutations in functionally related proteins, or from more than one mechanism.

Carcinoid tumour in a caecal duplication cyst.

Intestinal duplication cysts are rare congenital anomalies that may occasionally undergo neoplastic change. We report the case of a 30-year-old woman who was diagnosed to have a caecal duplication cyst. The cyst was excised and histology revealed the presence of a 10 mm diameter carcinoid tumour within the cyst wall. There was no evidence of metastatic spread and the patient remains well after 2 years follow-up. The 3 previously reported cases of carcinoid tumour arising within duplication cysts are reviewed.

Primary angiosarcomas of the chest wall and pleura.

Primary angiosarcomas of the chest wall and pleura are extremely rare and carry a dismal prognosis. Two cases are reported. One patient (case 1), presented with massive recurrent haemothorax, was found to have multifocal angiosarcoma of the pleura, treated with surgical de-bulking, chemical pleurodesis and chemotherapy, achieving control of the bleeding. She died 10 months later from complications related to chemotherapy. A full post-mortem examination confirmed this was a primary pleural angiosarcoma with no evidence of disease elsewhere. Another patient (case 2) with a large solitary angiosarcoma of the chest wall, discovered incidentally on a routine physical examination, was successfully treated with surgical excision and subsequent radical radiotherapy, remaining well 15 years post-operatively.

Transthoracic fine needle aspiration cytology of lung for suspected malignancy: an audit of cytological findings with histopathological correlation.

Transthoracic fine needle aspiration cytology (TFNAC) is an invasive procedure and should therefore be subject to regular review. We report an audit of TFNAC from 146 patients. One hundred and thirty-six samples (93%) were adequate and 86 were malignant, 16 suspicious and 34 contained no malignant cells. TFNAC was the sole means of diagnosis of malignancy in 55 patients. However, further pathological data were available in 58 of the adequate samples; TFNAC was malignant in 31, suspicious in eight and contained no malignant cells in 19. All malignant TFNAC were confirmed (absolute sensitivity = 85%; positive predictive value = 100%); as were five of eight with suspicious cytology. Of 19 patients with negative TFNAC, nine were subsequently found to have a malignancy (specificity = 68%).

p53 gene product expression in resected non-small cell carcinoma of the lung, with studies of concurrent cytological preparations and microwave antigen retrieval.

AIM: To document the frequency and extent of p53 gene product expression in paraffin sections of resected non-small cell carcinoma of the lung and in cytological preparations of the same tumours; to determine the effect of microwave antigen retrieval on antigen detection. METHODS: Representative paraffin sections of 50 non-small cell carcinomas were stained with an antibody to p53 gene product (DO-7) both with and without prior microwave antigen retrieval. Cytoblocks and cell smears obtained from 19 cases were similarly stained. RESULTS: Using a histochemical scoring system (0-300) which takes into account staining intensity and extent, 78% (n = 39) of microwave pretreated paraffin sections and 52% (n = 26) of non-pretreated sections scored between 5 and 300; p = 0.001; 56% (n = 28) of microwave pretreated sections and only 2% (n = 1) of non-pretreated sections scored between 100 and 300 (p = 0.0001); 75% of direct smears of tumours and 80% of cytoblocks stained similarly to the paraffin sections of the resected specimens. No smears or cytoblocks stained positively when the sections of the resected specimen were negative. CONCLUSIONS: As up to 78% of non-small cell lung carcinomas overexpress p53 gene product, this may prove to be a valuable diagnostic method in biopsy or cytological material when the morphological diagnosis is uncertain. Microwave antigen retrieval is effective on formalin fixed tissue.

A comparison of pathological methods of measuring lung cancer volume.

AIM: To determine which of several pathological methods of measuring lung cancer volume compared most favourably with the gold standard. METHODS: Three pathological methods were used on 54 resected lung cancers: (1) measuring the maximum dimension and assuming a spherical shape; (2) measuring three dimensions and assuming an ellipsoidal shape; and (3) deriving the volume from the area of tumour on sequential 1 cm slices using a photocopier and an image analysis system. The gold standard was obtained from the area of whole mount tumour sections on sequential 0.1 cm slices of eight cancers. RESULTS: Volumes derived from 1 cm lung slices gave results closest to our gold standard but assuming tumours were ellipsoidal was only a slightly less accurate and less time consuming method. Assuming cancers were spherical resulted in gross overestimation of the tumour volumes. CONCLUSIONS: For practical purposes, it is reasonable to measure three dimensions of a lung tumour at sectioning and calculate the volume using the formula for an ellipsoid (V = 4/3 pi d.e.f, where d, e and f are the semi-axes).

The photocopier: an overlooked tool in surgical pathology.

Pictorial representation of gross pathological specimens aids interpretation of many specimens in surgical pathology. The availability of such images is invaluable to subsequent review of material. Line diagrams are subjective and imprecise. Photographic recording of specimens is expensive, particularly if an instant image is required. A completely enclosed technique in which a plain paper photocopier is used to record images of gross pathological specimens is described together with appropriate applications in surgical pathology. The photocopier represents an inexpensive, rapid and reliable method of producing an acceptable permanent record of many gross specimens.

Lewy bodies in the brain of two members of a family with the 717 (Val to Ile) mutation of the amyloid precursor protein gene.

A second member of the original family with the valine to isoleucine substitution at codon 717 of the amyloid precursor protein died after the clinical diagnosis of Alzheimer's disease had been made in life. Neuropathological examination of the brain revealed not only severe Alzheimer type pathology, with senile plaques and neurofibrillary tangles, but also Lewy bodies both in the cortex and brainstem. Lewy bodies also occurred in our first case, thus showing striking similarities in these two members of the same family. The possibility exists that the occurrence of Lewy bodies may not be coincidental, but could be genetically determined: the same genetic abnormality which determines the deposition of beta A4 protein, thus triggering of a chain of events leading to Alzheimer's disease, may result in, or predispose to Lewy body formation.

Effects of inhaled capsaicin in heart-lung transplant patients and asthmatic subjects.

We have studied the effects on FEV1 of inhaled capsaicin in concentrations of 3 x 10(-6) to 3 x 10(-1) mg/ml and methacholine (1 to 16 mg/ml) in 15 heart-lung transplant (HLT) patients who had undergone recent transbronchial lung biopsy to determine the relationships in chronically denervated lungs between these different forms of airway hyperreactivity and inflammation. A total of 10 normal subjects and 17 asthmatic subjects were included for comparison. Capsaicin caused bronchodilation in eight HLT patients (FEV1 rising by 6.4 to 26.8%) and bronchoconstriction in two (fall in FEV1 of 7.2 and 7.6%). By contrast, seven asthmatic subjects developed bronchoconstriction after capsaicin (fall in FEV1 5.6 to 40.4%); the remaining 10 asthmatic subjects showed no response. Bronchial hyperresponsiveness to methacholine was most evident in the asthmatic subjects, but six HLT patients demonstrated a > or = to 20% fall in FEV1 with < or = 8 mg/ml of methacholine. All normal subjects were nonresponsive to both agents, and all normal and asthmatic subjects, unlike HLT patients, coughed with capsaicin. No relationship existed between the methacholine and capsaicin responses. In the HLT patients neither form of airway responsiveness was related to the degree of inflammation seen on transbronchial lung biopsy. The results suggest that in normal subjects, although it provokes cough, inhaled capsaicin causes little airway narrowing.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro pulmonary vasorelaxant effect of the phosphodiesterase inhibitor enoximone.

Enoximone is a phosphodiesterase inhibitor that has both positive inotropic and systemic vasorelaxant activities. The latter are mediated by an increase in vascular smooth muscle concentration of cyclic 3'5' guanosine monophosphate. However, the effect of enoximone on pulmonary vasoreactivity is not established. The authors, therefore, have studied its effect on endothelium-dependent relaxation mediated by the endothelium-derived relaxing factor nitric oxide (NO), as well as endothelium-independent relaxation of isolated porcine pulmonary arteries. Enoximone (10(-7) to 10(-4) M) caused a dose-dependent relaxation in all pulmonary arterial rings. This relaxation neither required the presence of the endothelium nor was affected by the addition of the inhibitor of NO synthase omega-nitro-L-arginine methyl ester (10(-4) M). Also, the vasorelaxant response of the rings to the endothelium-dependent vasodilator adenosine diphosphate (10(-10) to 10(-5) M) was not affected by pretreatment with enoximone. The authors conclude that enoximone is a potent vasodilator that relaxes pulmonary vascular rings through mechanisms independent of the endothelium. This endothelium-independent vasodilatory effect of enoximone makes it a potentially valuable drug for the treatment of pulmonary hypertension. This particularly applies to diseases in man where NO production by the endothelial cells is impaired.

Prospective study of transbronchial biopsies in the management of heart-lung and single lung transplant patients.

A prospective study of 219 bronchoscopies in 54 heart-lung and in 2 single lung transplant recipients was undertaken over a 12-month period by a single operator. For histologic study, an average of 17.3 transbronchial biopsy specimens (range, 6 to 56) were taken from three lobes (or from two lobes and lingula of one lung). A further two specimens were taken for culture. The average procedure time was 14.4 minutes (SE 0.31). An estimate of the probability of rejection being missed, depending on the number of specimens taken and based on the method of Gilman and Wang, suggests 18 biopsy specimens are required to have 95% confidence of diagnosing rejection. Sensitivity for diagnosing rejection by histologic study of transbronchial biopsy specimens was 94%, and specificity was 90%. The simple grading of severity of rejection that was used was related both to the number of specimens demonstrating rejection and to the severity of graft airway mucosal inflammation seen at bronchoscopy. The major complication encountered, on 27 occasions, was bleeding of more than 100 ml. On no occasion did bleeding result in any long-term complication. Extensive transbronchial biopsy is a simple, relatively safe, and quick procedure, with a high sensitivity and specificity for diagnosing rejection and lung infection.

Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease.

BACKGROUND: Endothelial cells release endothelium-derived relaxing factor (EDRF) in a variety of vascular beds, including the pulmonary circulation. However, the role of EDRF-mediated pulmonary-artery relaxation in chronic hypoxic lung disease is unknown. METHODS: We studied endothelium-dependent relaxation mediated by EDRF in vitro in pulmonary arteries that had been obtained from 22 patients undergoing heart-lung transplantation for end-stage chronic obstructive lung disease. Control pulmonary arteries were obtained from 15 patients undergoing lobectomy for lung carcinoma who did not have evidence of other chronic lung disease. The responses of all vascular rings (external diameter, 1.2 to 3.4 mm) to the endothelium-dependent vasodilators acetylcholine and adenosine diphosphate were studied immediately after lung excision. RESULTS: Pulmonary arterial rings from the patients with chronic lung disease developed a greater tension (2.19 +/- 0.16 g) in response to phenylephrine (10(-6) M) than the rings from control patients (1.28 +/- 0.18 g, P less than 0.05). Inhibition of EDRF synthesis by treatment with NG-monomethyl-L-arginine (10(-4) M) eliminated this difference, increasing the tension in the rings from the controls (P less than 0.01) but not in those from the patients with chronic lung disease. Rings from control patients relaxed in response to cumulative doses (10(-10) to 10(-5) M) of acetylcholine (maximal relaxation, 81.3 +/- 3.9 percent) and adenosine diphosphate (maximal relaxation, 85.3 +/- 2.6 percent). By contrast, rings from patients with chronic obstructive lung disease achieved only 41.3 +/- 4.8 percent of maximal relaxation in response to acetylcholine (n = 32) and 49.4 +/- 5.5 percent in response to adenosine diphosphate (n = 24) (P less than 0.001, as compared with control rings). Rings from both the controls and the patients with chronic lung disease relaxed similarly in response to the endothelium-independent vasodilator sodium nitroprusside (10(-4) M). There was an inverse correlation between the degree of intimal thickening and the level of maximal relaxation of the rings from the patients with chronic lung disease (r = -0.60, P less than 0.001). Maximal relaxation was also related directly to the partial pressure of arterial oxygen before transplantation (r = 0.68, P less than 0.01) and inversely to the partial pressure of arterial carbon dioxide before transplantation (r = -0.55, P less than 0.01), but not to the forced expiratory volume in one second (r = 0.19, P not significant). CONCLUSIONS: Endothelium-dependent pulmonary-artery relaxation in vitro is impaired in arteries from patients with end-stage chronic obstructive lung disease. Such impairment may contribute to the development of pulmonary hypertension in chronic hypoxic lung disease.

Risk factors for obliterative bronchiolitis in heart-lung transplant recipients.

Obliterative bronchiolitis is the major cause of death of long-term survivors of heart-lung transplantation. Of our first 75 patients who have received heart-lung transplantation, 38 have been followed for a year or longer. Eight patients developed clinical evidence of obliterative bronchiolitis within 15 months of transplantation, of whom four died with postmortem confirmation of extensive obliterative bronchiolitis, interstitial and pleural fibrosis, and vascular sclerosis in the heart and lungs. One further patient died before one year after chronic rejection. All nine patients had evidence on transbronchial biopsy of submucosal fibrosis and vascular sclerosis. Twelve of our remaining patients have shown similar areas of lung fibrosis on transbronchial biopsy, and the other eighteen are well and without fibrosis on transbronchial biopsy. Studies of the 274 biopsies obtained from 38 patients confirmed rejection on 182 occasions with more frequent, more persistent, and more severe rejection in the chronic rejection group than in the without-fibrosis or lung fibrosis groups. Opportunistic infection resulted in pneumonia on 19 occasions, and were most commonly found in lung fibrosis patients. We conclude that obliterative bronchiolitis is the likely outcome in patients with early, poorly controlled, severe rejection.

Natural history of chronic rejection in heart-lung transplant recipients.

Chronic rejection is the major cause of death of long-term survivors of heart-lung transplantation. Of our 61 patients who have received heart-lung transplants, 29 have been followed up for a year or longer. Seven patients had clinical evidence of chronic rejection within 15 months of transplantations of these seven, four died with postmortem confirmation of extensive obliterative bronchiolitis, interstitial and pleural fibrosis, and vascular sclerosis in the heart and lungs. All seven patients had evidence on transbronchial biopsy specimens of submucosal fibrosis and vascular sclerosis. Twelve of our remaining patients have shown similar areas of lung fibrosis on transbronchial biopsy specimens, and the other 10 are well and without fibrosis seen on transbronchial biopsy specimens. Studies of the 201 biopsy specimens obtained from 29 patients confirmed rejection on 130 occasions, with more frequent, more persistent, and more severe rejection in the chronic-rejection group than in the without-fibrosis or lung-fibrosis group. Opportunistic infections resulted in pneumonia on 19 occasions, and these were most commonly found in patients with lung fibrosis. We conclude that chronic lung rejection is the likely outcome in patients with early, poorly controlled, severe rejection.