Sex-related differences in bronchial epithelial changes associated with tobacco smoking.

BACKGROUND: Lung cancer is the most common cause of cancer death in North American women. Because smoking-related changes in the bronchial epithelium and in lung function have not been studied in detail in women, we used fluorescence bronchoscopy-directed biopsy to determine the prevalence of high-grade preinvasive lesions in former and current smokers of both sexes. METHODS: Spirometry, white-light bronchoscopy, and fluorescence bronchoscopy were performed in 189 women and 212 men older than 40 years of age who had smoked 20 pack-years or more (pack-years = number of packs of cigarettes smoked per day x number of years of smoking). RESULTS: Carcinoma in situ was found in 1.8% of the subjects, severe dysplasia was found in 6.5%, and moderate dysplasia was found in 14% (all preinvasive lesions). Compared with men, women had a lower prevalence of high-grade preinvasive lesions in the observed airways (14% versus 31%; odds ratio = 0.18; 95% confidence interval = 0.04-0.88), and women with preinvasive lesions had fewer such lesions (two-sided P = .048). The prevalence of preinvasive lesions did not change substantially for more than 10 years after cessation of smoking. Lung function was associated with the prevalence of preinvasive lesions, but the association was weaker in women than in men. If the presence of airflow obstruction was defined by an FEV1/FVC (forced expiratory volume in 1 second/forced vital capacity) value of 70% or less, only 56% of the men and 44% of the women with preinvasive lesions had abnormal lung function. CONCLUSION: In developing strategies for chemoprevention or early detection of lung cancer in high-risk populations, it is important to consider the effect of sex and arbitrarily chosen lung function values on the prevalence of preinvasive airway lesions.

Effect of filtration and concentration on the composition of bronchoalveolar lavage fluid.

The effects of filtration and concentration on the cellular and protein composition of bronchoalveolar lavage fluids were examined in ten normal subjects and 11 patients with asthma. Filtration of lavage fluid preferentially removed bronchial epithelial cells, resulting in a relative increase in the proportion of alveolar macrophages. Concentration of the lavage fluid results in a significant loss of proteins, with a greater loss of large molecular weight proteins. A similar loss was not observed when diluted sera form the same subjects were concentrated in the same manner. Our results suggest that when studying the cellular composition of bronchoalveolar lavage fluid, the aspirated fluid should not be filtered through cotton gauze if changes in the bronchial epithelium may be of importance because it will remove a significant proportion of these cells. Proteins in lavage fluids should be quantitated in unconcentrated lavage fluid whenever possible.

Effect of bronchial lavage volume on cellular and protein recovery.

To investigate the optimal lavage technique to study the airway response in patients with asthma, differential volume lavage was carried out in 22 normal subjects and 18 patients with red cedar asthma. Ten ml of fluid was instilled into a main-stem bronchus followed by 5, 10, 20, 50 and 100 ml into different segmental bronchi. Small volume lavage (less than 20 ml) in a main stem bronchus or a segmental bronchus recovered more epithelial cells and neutrophils while a lavage volume of 20-100 ml in a segmental bronchus recovered more lymphocytes, alveolar macrophages, albumin, IgG and alpha 1-antitrypsin. In patients with asthma, a higher proportion of epithelial cells was observed in the 20 ml segmental bronchus lavage 24 to 48 hours after bronchial challenge with plicatic acid, the chemical compound responsible for red cedar asthma. There was an increase in eosinophils and IgG with all volume lavages, but the changes were most marked in the 10 ml main bronchus lavage and the 10 and 20 ml segmental bronchus lavage. The results show the importance of using a systematic lavage protocol to characterize the cellular and protein changes in the airways of patients with asthma. A single volume lavage in one site may not encompass all the changes observed.

Localization of bronchial intraepithelial neoplastic lesions by fluorescence bronchoscopy.

BACKGROUND: In the treatment of lung cancer, the best outcome is achieved when the lesion is discovered in the intraepithelial (preinvasive) stage. However, intraepithelial neoplastic lesions are difficult to localize by conventional white-light bronchoscopy (WLB). OBJECTIVE: To determine if autofluorescence bronchoscopy, when used as an adjunct to WLB, could improve the bronchoscopist's ability to locate and remove biopsy specimens from areas suspicious of intraepithelial neoplasia as compared with WLB alone. METHOD: A multicenter clinical trial was conducted in seven institutions in the United States and Canada. WLB followed by fluorescence examination with the light-induced fluorescence endoscopy (LIFE) device was performed in 173 subjects known or suspected to have lung cancer. Biopsy specimens were taken from all areas suspicious of moderate dysplasia or worse on WLB and/or LIFE examination. In addition, random biopsy specimens were also taken from other parts of the bronchial tree. RESULTS: The relative sensitivity of WLB + LIFE vs WLB alone was 6.3 for intraepithelial neoplastic lesions and 2.71 when invasive carcinomas were also included. The positive predictive value was 0.33 and 0.39 and the negative predictive value was 0.89 and 0.83, respectively, for WLB+LIFE and WLB alone. CONCLUSION: Autofluorescence bronchoscopy, when used as an adjunct to standard WLB, enhances the bronchoscopist's ability to localize small neoplastic lesions, especially intraepithelial lesions that may have significant implication in the management of lung cancer in the future.

Ovarian carcinoma: a multivariate analysis of prognostic factors.

Five hundred and fifty six women with invasive epithelial ovarian carcinoma were assessed for postoperative treatment between 1966 and 1976. The records of this group were reviewed retrospectively. Sixteen characteristics of the patient and tumor were analyzed for prognostic significance by univariate and multivariate techniques. Tumor grade, the presence of residual disease, and patient performance status are identified as stage-specific independent prognostic factors. These independent factors define patient subsets with good, intermediate, and poor prognosis within each stage. The results show that more effective treatment strategies are required for patients in poor prognosis subsets. Estimates of tumor grade, extent of residual disease, and performance status should be included in reports of treatment outcome.

Differentiation of thyroid neoplasms by evaluating epithelial membrane antigen, Leu-7 antigen, epidermal growth factor receptor, and DNA content.

The expression of epithelial membrane antigen (EMA), Leu-7 antigen, epidermal growth factor receptor (EGFr), and deoxyribonucleic acid (DNA) content in 40 thyroid nodules was investigated to identify those factors that might differentiate these lesions or correlate to their prognosis. There were 22 carcinomas (16 papillary, 4 follicular, 1 anaplastic, 1 medullary) and 18 benign lesions prospectively obtained between 1989 and 1993. Patients' charts were reviewed to establish a database of known clinical prognostic indicators. Expression of EMA and Leu-7 was significant in malignant lesions when compared to benign lesions (P < 0.02 and P < 0.001). EMA was expressed significantly more frequently by follicular carcinomas than by follicular adenomas (P < 0.03). Leu-7 antigen was expressed by all papillary carcinomas. Neither of these antigens showed any association with known clinical prognostic indicators. EGFr expression neither differentiated benign from malignant lesions nor correlated with prognostic factors. The presence of aneuploidy correlated with poor tumor differentiation (P < 0.02), but did not distinguish benign from malignant lesions. These results suggest that EMA expression may be useful for confirming malignancy in follicular neoplasms and that the expression of Leu-7 antigen can assist in distinguishing papillary carcinoma from benign lesions with pseudopapillae.

An automated image cytometry system for monitoring DNA ploidy and other cell features of radiotherapy and chemotherapy patients.

DNA content and distribution in cell nuclei were studied in samples of fine-needle aspiration (FNA) from 27 locally advanced breast and head and neck cancers in two going randomized trials that compared accelerated fractionation to standard fractionation radiation in locally advanced breast cancer and head and neck cancer. Two image cytometry methods were compared: a new, fully automated DNA image cytometry system (AIC) and a conventional image cytometry (CIC) system with manual selection, focusing, and segmentation of cells. The results of both techniques were compared on the basis of DNA histogram parameters including DNA index (DI), mean DNA values (MDV), and Auer's DNA histogram patterns. An excellent correlation was achieved between the two imaging techniques in terms of DI (r=0.985, p<0.001) and MDV (r=0.951, p<0.001) as well as between Auer's histogram patterns, where both methods agreed completely. It was concluded in these analyses that the two image cytometry methods were equivalent. However, the AIC offered an advantage by scanning samples in a fully automated way, which represented significant time saving for cytopathologists working with the system, as well as a larger number of cells used in the automated analysis. With the automated image cytometer, 500 relevant cells were collected and analyzed in about 10 minutes, where with the interactive (manual) method, it took typically an hour to collect and analyze only about 250 cells. Seventeen samples were sufficient for flow analysis. Image cytometry and flow cytometry showed good agreement in DI determination; however, three cases reported as diploid by flow cytometry were found to be aneuploid by image cytometry techniques.

Autofluorescence of normal and malignant bronchial tissue.

In vivo autofluorescence spectra were obtained in 5 patients with carcinoma in situ, 26 patients with invasive tumors, and 1 patient with severe dysplasia. Significant spectral differences were observed between pre-cancerous, cancerous, and normal bronchial tissues. This difference may afford a method to image and/or detect early lung cancer by using tissue autofluorescence alone.

Detection and localization of early lung cancer by fluorescence bronchoscopy.

BACKGROUND: Curative therapy is available for patients with Stage 0 lung carcinoma, with a >90% 5-year survival rate. Promising chemopreventive agents also are under investigation currently to reduce the risk of lung carcinoma in high risk populations. However, preinvasive bronchial lesions (moderate to severe dysplasia and carcinoma in situ) are very small and thin. They are difficult to localize by conventional white-light bronchoscopy. Fluorescence bronchoscopy is a new diagnostic tool for the detection of these preinvasive lesions. METHODS: The data on the use of fluorescence bronchoscopy to detect and localize preinvasive lesions in current heavy smokers and in former smokers at the British Columbia Cancer Agency as well as the worldwide experience cited in MEDLINE, Index Medicus, and Deutsches Institut fur Medizinische Dokumentation und Information (Cologne, Germany) comparing white-light and fluorescence bronchoscopy using the lung imaging fluorescence endoscope (LIFE)-Lung device (Xillix Technologies Corp., Richmond, British Columbia, Canada) were reviewed. RESULTS: Among current heavy smokers and former smokers with sputum atypia, the prevalence of carcinoma in situ was 1.6%. Moderate or severe dysplasia was found in another 19%. The preinvasive lesions were found to be small: 55% measured < or = 1.5 mm in greatest dimension. Over 1000 cases have been reported in the literature between 1994 and 1999. Overall, 40% of the preinvasive lesions were detected by white-light bronchoscopy alone. The addition of fluorescence bronchoscopy increased the detection rate to an average of 80%. CONCLUSIONS: Preinvasive lesions, especially dysplastic lesions, are small. They are difficult to detect and localize by white-light bronchoscopy. Fluorescence bronchoscopy improves the detection rate. It is an important part of the armamentarium in the overall management of early lung cancer.

Release of leukotrienes in patients with bronchial asthma.

To investigate whether leukotrienes (LTs) are released into the bronchial fluid of patients with symptomatic asthma, bronchial lavage was carried out in 17 patients with mild to severe asthma and nine healthy subjects without asthma. LTE4 was detected in 15 of the 17 patients with asthma with reverse-phase high-performance liquid chromatography. The identify of LTE4 was confirmed by ultraviolet spectrometry and by positive ion fast atom-bombardment mass spectrometry. LTD4 was found in two patients and 20-OH-LTB4 in 12 patients. No LTs were detectable in the lavage fluid from any of the healthy subjects without asthma. The finding of LTs in bronchial lavage fluid from the patients with asthma despite bronchodilator and/or corticosteroid therapy suggests that these compounds may be important in asthma. However, the presence of significant quantities of LTE4 in patients with mild asthma requiring only intermittent bronchodilator therapy for control and the lack of correlation between LTE4 and pulmonary function also suggests that other factors may be important in determining the net end organ response. The present study points to the importance of studying the whole spectrum of mediators that are released. Analysis of bronchial lavage fluid may be useful in determining the relative role of these mediators and the effect of pharmacologic intervention.

Pigmented villonodular synovitis in multiple joints. Occurrence in a child with cavernous haemangioma of lip and pulmonary stenosis.

A case is presented of pigmented villonodular synovitis involving three joints in a 7-year-old girl. The diagnosis was confirmed at surgery and by histology. The patient also exhibited a haemangioma of the upper lip and a congenital pulmonary stenosis of mild degree. Subtotal synovectomy of the right knee and of both ankles was performed. The lesion recurred in both ankles after 6 months. Review of the literature failed to reveal any previous report of multiple joint involvement by pigmented villonodular synovitis in childhood and it appears that simultaneous involvement of three joints has not previously been described. Scintiscanning with 99mTc stannous pyrophosphate showed increased vascularity of the involved joints immediately after injection, but no increased osteoblastic activity was seen on the delayed scan. This radionuclide scanning technique is therefore helpful in distinguishing pigmented villonodular synovitis from other arthropathies.

Early localization of bronchogenic carcinoma.

The performance of a fluorescence imaging device was compared with conventional white-light bronchoscopy in 100 patients with lung cancer, 46 patients with resected stage I non-small cell lung cancer, 10 patients with head and neck cancer, and 67 volunteers who had smoked at least 1 pack of cigarettes per day for 25 years or more. Using differences in tissue autofluorescence between premalignant, malignant, and normal tissues, fluorescence bronchoscopy was found to detect significantly more areas with moderate/severe dysplasia or carcinoma in situ than conventional white-light bronchoscopy with a similar specificity. Multiple foci of dysplasia or cancer were found in 13-24% of these individuals. Fluorescence bronchoscopy may be an important adjunct to conventional bronchoscopic examination to improve our ability to detect and localize premalignant and early lung cancer lesions.

Malignancy-associated changes in bronchial epithelial cells in biopsy specimens.

A total of 152 normal bronchial biopsy sections--63 from normal subjects, 42 from patients with dysplasia, 28 from patients with early or advanced lung cancer with squamous and nonsquamous histopathology, and 19 from resected lung cancer patients--were examined for the presence of malignancy-associated changes (MACs). A standard, white light bronchoscope examination and a multispectral fluorescence bronchoscope examination were performed on every subject to determine the status of the bronchial epithelial tissue. Any suspect areas were biopsied to determine the status of the area and to establish the highest grade of abnormality in the patient. In addition, for every subject, a bronchoscopically normal area of the bronchus in the opposite lung or another lobe was biopsied. The specimens were confirmed to be normal by conventional histopathologic criteria using hematoxylin and eosin stain. Sections of biopsies were stained using a DNA stoichiometric stain, and approximately 250 images of visually normal epithelial cell nuclei from each of the biopsies were collected, as were approximately 40 images of leukocyte cell nuclei. For each of these images > 60 nuclear features were calculated that quantified the size, shape and DNA volume of the nuclei as well as DNA spatial organization in the nuclei. The features were then used to train an automated classifier to recognize normal epithelial cell nuclei from normal subjects and normal-appearing epithelial cell nuclei (MAC cell nuclei) from lung cancer patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in mediator release between allergic rhinitis and asthma.

To determine why patients with allergic rhinitis alone differ in their airway response to inhaled allergen compared to patients with allergic asthma, bronchial lavage was performed in 10 subjects with allergic asthma and in five subjects with allergic rhinitis, before and after inhalation challenge with antigen to produce an immediate asthmatic reaction. Before antigen challenge, the subjects with asthma had higher absolute neutrophil counts in the lavage fluid. After antigen challenge, the subjects with asthma released significant amounts of bronchoconstrictive mediators, such as histamine and thromboxane B2 into the lavage fluid, whereas subjects with rhinitis alone did not. There was also a significant increase in prostaglandin E2 in the subjects with asthma after antigen challenge. Nonimmunologic bronchoconstriction with methacholine inhalation challenge in six other subjects with asthma did not demonstrate an increase in any of the lavage fluid mediator levels that were measured. A positive correlation was found between methacholine provocative concentration causing a 20% drop in FEV1 and the concentration of prostaglandin E2 in the lavage fluid before challenge. The significance of this observation has yet to be determined. The results suggest that subjects with allergic asthma differ from subjects with rhinitis alone in their capacity to release more mediators into the airways on antigen challenge. It is not known whether this increase in mediators is due to increase in the number of mast cells in the airways or due to increase in mediator releasability from the mast cells of subjects with asthma.

Predicting the response of obstructive endobronchial tumors to photodynamic therapy.

To investigate the usefulness of bronchoscopic examination, computerized tomography (CT), and radionuclide quantitative ventilation-perfusion lung scan to determine the response of patients with obstructive endobronchial tumors to photodynamic therapy (PDT), the findings in 24 patients treated with PDT were analyzed. PDT was found to be most effective when the tumor was bronchoscopically polypoid in appearance, with little or no submucosal invasion or peribronchial extension seen on CT scans. With increasing submucosal and/or peribronchial extension, the immediate response to treatment was poorer. Patients who had 50% or more of the airway obstruction due to mucosal tumor had no evidence of local tumor recurrence for a median interval of 22 weeks after treatment. In patients with predominant submucosal and/or peribronchial tumor, the duration of response was 7 weeks. Response to treatment did not correlate with the degree of airway obstruction. CT provided valuable information regarding the extent of the peribronchial involvement and airway distortion, which was often underestimated by bronchoscopy alone. Absent perfusion or reduction of regional perfusion out of proportion to ventilation on scintigraphy in the involved lung zone was found to be associated with extensive peribronchial involvement and a poor outcome. The authors conclude that the addition of CT and radionuclide quantitative ventilation-perfusion lung scan to bronchoscopic examination is useful in predicting the response of patients with obstructive endobronchial tumors to PDT.

Detection of dysplasia and carcinoma in situ by ratio fluorometry.

Fluorescence bronchoscopy was performed in 82 volunteers recruited from occupational groups at risk of exposure to asbestos and/or diesel fumes to determine whether differences in tissue autofluorescence between normal and malignant bronchial tissues can be used to improve the sensitivity of standard fiberoptic bronchoscopy in detecting dysplasic and carcinoma in situ (CIS). This study consisted of 25 nonsmokers, 40 exsmokers, and 17 current smokers with mean ages of 52, 55, and 49 yr, respectively. Tissue autofluorescence was induced by a blue light from an He-Cd laser coupled to the illumination channel of the bronchoscope and analyzed by a ratiofluorometer. One or more sites of moderate or severe dysplasia were found in 12% of the exsmokers and current smokers but in none of the nonsmoker volunteers. CIS was found in two of the exsmokers. The sensitivity of fluorescence bronchoscopy (86%) was found to be 50% better than that of conventional white-light bronchoscopy (52%) in detecting dysplasia and CIS. Pre- and post-bronchoscopy sputum cytology failed to detect these precancerous lesions. Our results suggest that fluorescence bronchoscopy may be an important new method that can improve the ability to detect and localize precancerous and/or CIS lesions.

Cytological aspects of uterine cervical adenocarcinoma, adenosquamous carcinoma and combined adenocarcinoma-squamous carcinoma: appraisal of diagnostic criteria for in situ versus invasive lesions.

This paper reports the cytological findings based on air-dried smears in a retrospective series of 143 cases of endocervical adenocarcinoma, combined adenocarcinoma-squamous carcinoma and adenosquamous carcinoma drawn from the files of the BC Cancer Registry. Cervical cytology smears were available before biopsy in 131 patients, but in 18 cases the cytology showed no abnormality. Malignant changes or high-grade atypia of glandular and/or squamous cells (defined as moderate or severe dyskaryosis) were detected in 103 cases. In 46 cases, only a high-grade squamous abnormality was detected. Low-grade glandular and/or squamous lesions were detected in nine cases and one showed atypical endometrial-type glands. The cervical smears of 64 cases were reviewed in detail to determine the important cytomorphological criteria of in situ and invasive adenocarcinoma in air-dried smears, the technique used for preparing PAP smears in British Columbia. Endocervical cells were absent in four cases. Numerous (> 10) groups of glandular cells were present in 51 cases. Important clues to the diagnosis of adenocarcinoma included crowding of nuclei, stratification of nuclei, loss of polarity, syncytial balls and papillary groups of glandular cells, nuclear enlargement, nuclear pleomorphism, and the presence of free-lying atypical glandular cells. Nuclear hyperchromatism, chromatin pattern, nuclear borders, nuclear membranes, and numbers and morphology of nucleoli were not helpful criteria in our material. Criteria enabling reliable distinction between in situ and invasive adenocarcinoma and/or mixed adenocarcinoma-squamous carcinoma could not be established.

Laser treatment of obstructive endobronchial tumors: factors which determine response.

To investigate whether computerized tomography (CT) and radionuclide quantitative ventilation-perfusion lung scan add any useful information to a carefully performed endoscopic examination in determining the response of patients with obstructive endobronchial tumors to laser treatment, the findings in 40 patients treated with photodynamic therapy (PDT) or the Nd:YAG laser were analysed. Endoscopic laser treatment was found to be most effective when the tumor was polypoid in appearance bronchoscopically, with little or no submucosal invasion or peribronchial extension seen on CT. When bronchoscopy and CT showed increasing submucosal and/or peribronchial disease, the immediate and long-term response to treatment was poorer. CT provided valuable information regarding the extent of the peribronchial involvement and airway distortion which were often underestimated by bronchoscopy alone. Reduction of regional perfusion out of proportion to ventilation on scintigraphy in the involved lung zone was found to be associated with extensive peribronchial involvement. We conclude that the addition of CT and radionuclide quantitative ventilation-perfusion lung scan to bronchoscopic examination is useful in predicting the response of patients with obstructive endobronchial tumors to laser treatment. Whether PDT or YAG laser is more effective in relieving endobronchial obstruction by tumor awaits a randomized controlled trial.