Molecular detection of primary bladder cancer by microsatellite analysis.

Microsatellite DNA markers have been widely used as a tool for the detection of loss of heterozygosity and genomic instability in primary tumors. In a blinded study, urine samples from 25 patients with suspicious bladder lesions that had been identified cystoscopically were analyzed by this molecular method and by conventional cytology. Microsatellite changes matching those in the tumor were detected in the urine sediment of 19 of the 20 patients (95 percent) who were diagnosed with bladder cancer, whereas urine cytology detected cancer cells in 9 of 18 (50 percent) of the samples. These results suggest that microsatellite analysis, which in principle can be performed at about one-third the cost of cytology, may be a useful addition to current screening methods for detecting bladder cancer.

Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance.

BACKGROUND: Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. PURPOSE: We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. METHODS: A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. RESULTS: No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.

Prospective detection of preclinical lung cancer: results from two studies of heterogeneous nuclear ribonucleoprotein A2/B1 overexpression.

The United States lung cancer epidemic has not yet been controlled by present prevention and treatment strategies. Overexpression of a Mr 31,000 protein, heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, had shown promise as a marker of lung cancer. In a pilot study of archived preneoplastic sputum specimens, hnRNP A2/B1 overexpression more accurately detected preclinical lung cancer than standard cytomorphology. In separate, ongoing prospective studies, sputum is collected annually from stage I resected non-small cell lung cancer patients at high risk of developing a second primary lung cancer and Yunnan tin miners at high risk of primary lung cancer. After the first year of follow-up, preclinical detection of lung cancer by routine cytology was compared with hnRNP A2/B1 overexpression as measured by quantitative densitometry of immunostained slides. Up-regulation of hnRNP A2/B1 in sputum specimens accurately predicted the outcome in 32 of 40 primary lung cancer and control patients within 12 months, whereas cytological change suggestive of lung cancer was found in only 1 patient. In the primary lung cancer study, overexpressed hnRNP A2/B1 accurately predicted the outcome in 69 of 94 primary lung cancer and control miners, whereas only 10 with primary lung cancer were diagnosed cytologically. These two prospective studies accurately predicted that 67 and 69% of those with hnRNP A2/B1 up-regulation in their sputum would develop lung cancer in the first year of follow-up, compared with background lung cancer risks of 2.2 and 0.9% (35- and 76-fold increase, respectively). Using sputum cells to monitor hnRNP A2/B1 expression may greatly improve the accuracy of preclinical lung cancer detection.

A case-cohort study of an early biomarker of lung cancer in a screening cohort of Yunnan tin miners in China.

We initiated the present study to evaluate the accuracy of a new epithelial biomarker of early lung cancer. We tested the hypothesis that expression of a tumor-associated antigen by exfoliated sputum epithelial cells has greater accuracy (sensitivity and specificity) for the detection of preclinical, localized lung cancer than do routine clinical detection methods. Monoclonal antibody (MAb) 703D4 recognizes heterogeneous nuclear ribonuclear protein (hnRNP) A2/B1. We compared the accuracy of hnRNP up-regulation with cytology and radiographic screening for lung cancer detection in miners who were highly exposed to tobacco smoke, radon, and arsenic in southwestern China. The results showed that MAb 703D4 detection of hnRNP expression by sputum epithelial cells had greater accuracy for the detection of lung cancer than did routine screening methods, particularly for early (localized) disease. Among 57 cases and 76 noncases at the first screening, overall MAb detection of hnRNP was more sensitive (74 versus 21% for cytology and 42% for chest x-ray) but had lower specificity (70 versus 100% for cytology and 90% for chest x-ray) than standard methods. Recognizing hnRNP up-regulation resulted in detection of approximately one-third more early cases than did the combination of X-ray and cytology. Detection of hnRNP A2/B1 expression appears to be a good initial screening test for lung carcinogenesis, as it identified 74% of those who developed subsequent clinical lung cancer. Future studies might separate individuals with high lung cancer risk by MAb detection, confirming the positives with markers having greater specificity (e.g., clinical studies that become positive later in the morphological progression).

Polymorphisms of the DNA repair gene XRCC1 and lung cancer risk.

We explored the association between polymorphisms of the DNA repair gene XRCC1 (codons 194, 280, and 399) and lung cancer risk in a case-control study nested within a cohort of tin miners. Cases were those diagnosed with lung cancer over 6 years of follow-up (n = 108). Two controls, matched on age and sex, were selected for each case by incidence density sampling. Of the three polymorphisms, only the XRCC1 Arg280His allele was associated with increased lung cancer risk (odds ratio, 1.8; 95% confidence interval, 1.0-3.4) after adjustment for radon and tobacco exposure. In addition, individuals with the variant Arg280His allele who were alcohol drinkers seemed to be at higher risk for lung cancer compared with those with the homozygous wild-type genotype. Conversely, individuals with the variant Arg194Trp allele who were alcohol drinkers seemed to be at lower risk for lung cancer compared with those with the homozygous wild-type genotype. Polymorphisms of XRCC1 appear to influence risk of lung cancer and may modify risk attributable to environmental exposures.

Risk factors and early detection of lung cancer in a cohort of Chinese tin miners.

PURPOSE: To examine risk factors and establish a biologic specimen and data bank for the study of early markers of lung cancer. METHODS: We designed a dynamic cohort using an ongoing lung cancer screening program among radon- and arsenic-exposed tin miners in Yunnan China. Through the first four years of the study, 8,346 miners aged 40 years and older with over 10 years of occupational exposure have been enrolled, risk factors have been assessed, annual sputum and chest radiographs have been obtained, and numerous biologic specimens have been collected. RESULTS: A total of 243 new lung cancer cases have been identified through 1995. Radon and arsenic exposures are the predominant risk factors, but lung cancer risk is also associated with chronic bronchitis and silicosis, as well as a number of exposure to tobacco smoke, including early age of first use, duration, and cumulative exposure. Tumor and sputum samples are being examined for early markers of lung cancer. CONCLUSION: A cohort of occupationally-exposed tin miners with an extensive biologic specimen repository has been successfully established to simultaneously study the etiology and early detection of lung cancer.

A new versatile transbronchial cytology needle for the staging and diagnosis of bronchogenic carcinoma.

A new versatile transbronchial needle, the modified type 2B retractable needle, was used for the staging and diagnosis of bronchogenic carcinoma. It combines the advantages of its predecessors, the fixed type 1A needle and the retractable type 2A needle, such as convenience of usage and the added ability to sample peripheral as well as central lesions. The new modified type 2B retractable needle provides better protection of the airways and bronchoscope than the fixed type 1A needle and eliminates the type 2A needle's requirement for total removal of the guidewire before aspiration. The new type 2B needle was compared with either the original fixed type 1A or the retractable type 2A needle in 20 patients at 34 transbronchial sites and found a similar diagnostic yield. The modified type 2B retractable needle was the most versatile needle of those studied and can be used for transbronchial needle aspiration of both central and peripheral lesions.

Efficacy of pleural needle biopsy and pleural fluid cytopathology in the diagnosis of malignant neoplasm involving the pleura.

A comparison was made of the efficacy of pleural needle biopsy and pleural-fluid cytopathology in the diagnosis of pleural tumor in a group of 271 patients. A malignant tumor involving the pleura was present in 95 cases. Needle biopsy alone provided a diagnosis of tumor in 53 instances, and cytopathologic preparations were diagnostic in 69 patients. A diagnosis was established on either the biopsy or cytopathology, or both, in 86 cases (90 percent). These results indicate the value of using both biopsy and fluid cytology in the evaluation of pleural effusion, which often is due to involvement of the pleura by malignant neoplasm.

The early detection of second primary lung cancers by sputum immunostaining. LCEWDG Investigators. Lung Cancer Early Detection Group.

STUDY OBJECTIVE: To determine whether monoclonal antibody (Mab) detection of tumor-associated antigen expressed on sputum epithelial cells precedes clinical presentation of second primary lung cancer. DESIGN SETTING/PARTICIPANTS: Eleven oncology centers collaborate in the accrual of 1,000 patients with stage I non-small cell lung cancer (NSCLC) who had undergone resection. The Mabs examined in this study (624H12, 703D4) detect two promising oncofetal/differentiation markers (ie, a difucosylated Lewis X and a 31-Kd glycoprotein antigen). INTERVENTIONS: Induced sputum specimens are evaluated for quality, then are Papanicolaou and immunostained by independent central laboratories at enrollment and annually thereafter. The predictive value of Mab markers is compared with routine morphologic study for detection of second primary lung cancer during an anticipated 3 years of accrual and 1 year of follow-up. MEASUREMENTS AND RESULTS: Five hundred eighty of an anticipated 1,000 patients have been accrued on schedule. Patients are primarily white (88.6%), former smokers (75.9%), men (55.6%), with a median age of 66.7, and joined the study at an average of 3.7 years following resection of a stage 1 NSCLC (34.4% squamous, 43.6% adenocarcinoma). Central laboratories found less dysplasia and more unsatisfactory specimens (27.3%) than do the accrual institution laboratories. Immunostaining identifies more suspicious cells than does morphologic study. However, only two second primary lung cancers (eight total deaths) have occurred to date. CONCLUSIONS: Halfway through the accrual, we describe the study design and preliminary observations. This study illustrates rational selection of carcinogenesis markers by linkage of marker expression on preneoplastic specimens with subsequent expression on tumor tissue.

Transbronchial needle aspiration of peripheral pulmonary nodules.

To determine the role of transbronchial needle aspiration (TBNA) in the diagnosis of peripheral pulmonary lesions, TBNA was performed in 20 patients who had unexplained nodules (15) or masses (five) and no endobronchial abnormality. The TBNA cytopathology was positive for malignancy in 11 patients, and provided the only diagnostic specimen in seven. The TBNA yield was significantly higher than that of forceps biopsy or bronchial brushing, either alone or in combination (p less than 0.05). The procedure was complicated by pneumothorax in one patient. Transbronchial needle aspiration is diagnostically useful and safe for evaluation of the peripheral pulmonary nodule.

Transbronchial needle aspiration for diagnosis of lung cancer.

Thirty-two consecutive patients with mediastinal lesions suggestive of bronchogenic carcinoma underwent transbronchial needle aspiration. Eighteen of 20 patients (90 percent) with proved bronchogenic carcinoma had malignant cytology specimens or tissue fragments. Of 12 patients with normal cytology specimens, six were subsequently proved to have nonneoplastic disease. Transbronchial needle aspiration appears to offer a sensitive and specific alternative to more invasive surgical techniques used in the diagnosis of malignancies with mediastinal involvement.

The value of immediate cytologic evaluation for needle aspiration lung biopsy.

RATIONALE AND OBJECTIVES: The authors evaluate the role of immediate cytologic evaluation (ICE) with fine-needle aspiration biopsy (FNAB) for lung lesions at highest risk for pneumothorax. METHODS: A prospective randomized study was conducted of 80 patients with lung lesions surrounded by aerated parenchyma undergoing FNAB with and without ICE (47 and 33 patients, respectively). An analysis of needle passes, procedure time, complications, specimen adequacy, diagnostic yield, and accuracy of procedure was made. RESULTS: There was an increased number of needle passes with ICE (> or = three passes: 23% [11 biopsies] versus 3% [1 biopsy]; P = 0.01). Fluoroscopic procedures took longer with ICE (median time: 15 versus 9 minutes; P = 0.002) with no difference in complication rates. Specimen adequacy was similar (74% and 64%) and the procedure was diagnostic in 79% (37 biopsies) with ICE and in 70% (33 biopsies) without ICE. There were no significant differences in the sensitivity, specificity, or accuracy of the biopsy. CONCLUSIONS: Immediate cytologic evaluation improved results marginally with increased procedure time and needle passes. Immediate cytologic evaluation may be most useful for lesions at lowest risk of complications to assure that a second procedure is not required.

The role of the saccomano technique in sputum cytopathologic diagnosis of lung cancer.

The Saccomanno technique of sputum preparation is widely used. This study evaluates the role of this preparation in conjunction with fresh smears in the diagnosis of lung cancer. All sputum samples from September 1973 to July 1975 showing atypia were randomized and negative controls added. The Saccomanno and fresh smears were evaluated independently and blindly and classified as negative, atypical, suspicious, or cancer. When each preparation was compared with the original diagnosis, the diagnostic accuracy for 55 squamous carcinomas was similar (fresh 95%, Saccomanno 86%) but significantly less in the Saccomanno preparations of 22 small cell carcinomas (fresh 100%, Saccomanno 24%) and 26 adenocarcinomas (fresh 96%, Saccomanno 52%). Four cases negative on fresh smears were suspicious or diagnostic of cancer on the Saccomanno slides. There were no cases of small cell carcinoma in which the Saccomanno preparations added information not available on the fresh smears. The authors conclude that in conjunction with fresh smears, the Saccomanno preparation may contribute to the diagnosis of non-small cell carcinomas but does not appear to aid in the diagnosis of small cell carcinoma.

Fine-needle aspiration of the liver. A comparison of smear and rinse preparations in the detection of cancer.

Fifty-nine successive cases of fine-needle aspiration (FNA) of the liver were reviewed to determine the efficacy of various rinse and smear preparations in rendering a diagnosis of cancer. Preparations included Papanicolaou- and Diff-Quik-stained smears, Millipore filters, cytocentrifugation, and cell blocks. Of 33 of 59 cases diagnostic for cancer, 90% were positive on rinse, 78% on smear, and 69.6% on both rinse and smear. Seven cases (21.2%) were diagnostic on rinse preparation only and would otherwise have been interpreted as equivocal. Papanicolaou smears and cell block rinses were most valuable to evaluate malignancy in the liver, using the FNA technic. The authors believe rinse preparations justify their cost for assessment of cancer and are essential to establish the diagnosis in a significant number of cases.

Diagnostic value of cytopathology in Barrett esophagus and associated carcinoma.

Barrett esophagus, the columnar-lined distal esophagus acquired as a consequence of chronic gastroesophageal reflux, is associated with the development of columnar epithelial dysplasia and esophageal adenocarcinoma. To determine the efficacy of cytopathology in identifying Barrett esophagus and related neoplasia, observations were compared on 150 esophageal cytology samples with concurrent endoscopic biopsy specimens. Sixty-six specimens that contained benign columnar epithelium in either cytologic or biopsy material were identified. Distinctive-type Barrett mucosa with incomplete intestinalization, considered diagnostic of Barrett esophagus, was found in 34 of 66 cases (52%) and was present only in cytologic material in 11 cases. Twenty-two specimens contained cardiac-type mucosa (present only in cytology in ten cases), a finding of uncertain significance due to lack of localization of the sample with respect to the gastroesophageal junction. Fundic-type mucosa was not observed in any specimen. Two cases of distinctive-type Barrett mucosa with columnar epithelial dysplasia were identified in both biopsy and cytology specimens. Among eight Barrett-associated carcinomas (seven adenocarcinomas and one squamous), cytologic material was diagnostic for malignancy in seven and highly suspicious in one. It was concluded that cytopathologic studies are a useful adjunct to biopsy histopathology in the diagnosis of Barrett esophagus and associated carcinoma. The role of cytopathology in the diagnosis of Barrett-related columnar epithelial dysplasia requires further study, and at present a cautious approach with biopsy confirmation is recommended.

Fine-needle aspiration cytology of monomorphic adenomas.

The diagnostic accuracy of fine-needle aspiration of salivary gland lesions is now widely accepted. The cytologic appearance of two rare monomorphic variants of pleomorphic adenomas is described. The trabecular-tubular adenoma consisted of a trabecular arrangement of uniform small cells with scant basophilic cytoplasm and round nuclei. No mucoid spheres were present. The canalicular adenoma also had a distinctive cytologic appearance consisting of papillae and interconnected canaliculi lined by a layer of columnar epithelium. Monomorphic adenomas have unique morphologic appearances that can be recognized in fine-needle aspiration cytology. Preoperative diagnosis can greatly aid the surgeon in the planning of definitive surgical excision of salivary gland neoplasms.

Stereotactic brain biopsy in the diagnosis of malignant lymphoma.

Fifteen patients with cerebral involvement by malignant non-Hodgkin's lymphoma were identified, among more than 200 patients who underwent stereotactic biopsy at The Johns Hopkins Hospital. All but one of these cases were diagnosed accurately by the stereotactic biopsy procedure. In 12 of 14 patients, the material was adequate to classify the lymphoma according to the Working Formulation. Because all but one of the lesions were intermediate or high-grade neoplasms, a diagnosis of lymphoma was often possible by conventional light microscopic examination alone. Monotypic light chain expression was demonstrated by immunohistochemical techniques in six patients, and positivity for B-cell markers was observed in an additional case. In one instance, two stereotactic biopsy specimens were interpreted as being suggestive of lymphoma, but necrosis and inflammation prevented a definitive diagnosis. Nine patients had no known risk factors for cerebral lymphoma, and the diagnosis often was unsuspected clinically.

Adenocarcinoma arising in adenomyosis detected by atypical cytology.

Adenocarcinoma in adenomyosis is unusual and in most cases is associated with adenocarcinoma in the surface endometrium. In the latter, the diagnosis is made in the removed specimen because of the finding of adenocarcinoma in curettings. In contrast, adenocarcinoma arising in adenomyosis without surface endometrial changes is extremely rare and presents major diagnostic problems. The two cases reported herein demonstrate the significance of atypical vaginal cytology in the recognition of such lesions.

Microinvasive cervical cancer after five negative Papanicolaou smears.

In view of the controversy regarding the appropriate frequency for cytologic screening, a 28-year-old woman who developed microinvasive carcinoma of the cervix less than one year after her fifth negative Papanicolaou smear is described. The lesion was found not high in the endocervical canal, but at the squamocolumnar junction well out on the portio of the cervix. This case documents that the risk of less frequent screening is not zero.

Use of laboratory reports to assess cervical cancer screening in a community.

Cancer of the uterine cervix, the sixth most common cancer among women, is still considered a significant health problem, despite declining mortality rates during recent decades. In Baltimore, the age-adjusted mortality rates for cervical cancer are significantly higher than the U.S. average, for both black and white women. Early detection of cervical cancer through screening with the Papanicolaou (Pap) test has shown to decrease mortality by preventing development of invasive disease, and intervention programs have been developed to increase use of Pap testing. However, the evaluation of those programs is difficult, as self-reports of Pap screening may be inaccurate, and repeated inquiries about Pap tests may influence the behavior being studied. We report in this article a method to use data from cytopathology laboratories to estimate the use of Pap screening by women in a defined population. This approach can be used to evaluate changes in receipt of Pap smears and to provide feedback to intervention programs.