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.

Herpes simplex virus infection in heart-lung transplant recipients.

We report our experience of herpes simplex virus infection in a series of 51 recipients of heart lung transplantation (HLT). Nine patients, all of whom were seropositive for the virus preoperatively, developed HSV infection. Seven episodes of culture-proved mucocutaneous HSV infection without evidence of pulmonary involvement occurred in four patients. Six episodes of HSV pneumonia were seen in a further five patients, one of whom died. Diagnosis of HSV pneumonia was by histological appearances on transbronchial biopsy, together with culture of lung tissue or bronchoalveolar lavage. Concomitant cytomegalovirus infection occurred in four patients. All patients who developed HSV pneumonia did so within the first two postoperative months; in four patients following augmented immunosuppression. We now suggest that HLT recipients who are HSV antibody-positive should receive prophylactic acyclovir for the first two months after surgery and at times of augmented immunosuppression.

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.

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.

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).

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.

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.

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.

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.

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.

Histological differentiation of metastatic renal carcinoma in the cerebellum from cerebellar haemangioblastoma in von Hippel-Lindau's disease.

Two cases of von Hippel-Lindau's disease with special reference to the occurrence of renal carcinoma are presented. The first case demonstrates the difficulty of differentiating cerebellar haemangioblastoma from metastatic renal carcinoma affecting the cerebellum. The valuable differentiating histological features were positive staining of metastatic renal carcinoma by antiepithelial membrane antigen (anti-EMA) and the demonstration of a distinct pattern of packeting of cells by staining reticulin fibres. Staining with periodic acid Schiff and cytokeratin antibody (anti-CK) were not found to be useful. The second case exhibits the wide variety of neoplasms which may be present in von Hippel-Lindau's disease. Special stains support the findings of the first case.

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%).

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)

The histological changes in transbronchial biopsy after treatment of acute lung rejection in heart-lung transplants.

Transbronchial lung biopsies taken during episodes of acute lung rejection in heart-lung transplant patients were examined histologically. When the diagnosis was confirmed by microscopy, the patients were treated with augmented immunosuppression by high-dose corticosteroids. A second biopsy was obtained an average of 23.5 days after commencement of treatment. These biopsies were examined to determine the histological changes caused by treatment. In most cases, there were both quantitative and morphological differences between the infiltrates in acute rejection and in the remaining perivascular infiltrates after treatment. In acute rejection, 26 of 28 biopsies contained perivascular lymphocytic infiltrates, lymphocytes being large and blast-like. Although 20 of 28 follow-up biopsies still contained perivascular infiltrates, they were smaller and the lymphocytes smaller in size. Half the biopsies in rejection contained neutrophils, but less than half contained eosinophils in the perivascular infiltrates. After treatment, all these cells were less numerous. Another feature of treated rejection was the presence of haemosiderin around vessels suggesting earlier acute vascular injury. However, haemosiderin persists long after the cellular infiltrate has disappeared and cannot be considered a reliable feature of recently treated acute lung rejection. The bronchiolar infiltrates showed a similar pattern of responses to the perivascular infiltrates.

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.

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.