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.

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).

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.

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 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.

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.

Cul-de-sac fluid in women with endometriosis: fluid volume and prostanoid concentration during the proliferative phase of the cycle--days 8 to 12.

Cul-de-sac fluid from women with histologically confirmed endometriosis (n = 45) or with no evidence of endometriosis (n = 17) was removed during the proliferative phase of the menstrual cycle (days 8 to 12) and analyzed for prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), 15-keto-13,14-dihydroprostaglandin F2 alpha (PGFM), and thromboxane B2 (TXB2). The fluid volume was recorded. Peripheral blood was also obtained to determine the concentration of PGFM. Prostanoid concentrations (PGE2, PGF2 alpha, PGFM, TXB2) in women with endometriosis were not significantly different from a comparable group of disease-free women. Furthermore, a meaningful elevation of prostanoid with increasing severity of disease could not be demonstrated. Plasma PGFM was not significantly different from controls. There was, however, an elevation of PGFM with severity of disease, although this increase was not statistically significant (P = 0.11). An increase in fluid volume was not demonstrated in women with endometriosis, as compared with controls.

Quality control in cytopathology.

Quality control in cytopathology involves specimen collection, preparation, screening, and final diagnosis. The measures to assure the optimal performance and to detect the malfunctions in these areas are discussed. Careful selection and application of proper procedures, proper training and continuing education of cytotechnologists and pathologists, and reasonable workload for screening cytotechnologists and important factors in quality assurance.

Utility of immediate on-site cytopathological procurement and evaluation in fine needle aspiration biopsy of head and neck masses.

The utility of on-site microscopic evaluation of fine needle aspirates (FNAs) of the head and neck was assessed by comparing the diagnostic yield in 336 specimens obtained with immediate on-site cytopathological procurement and evaluation to that achieved in 548 cases performed without immediate on-site evaluation. Three hundred six (91%) of 336 immediate evaluation specimens were adequate for cytopathologic diagnosis, compared to 391 (71%) of 548 specimens not evaluated immediately (P < .001, chi-squared test). The higher satisfactory rate in immediate evaluation cases was related primarily to 1. immediate reaspiration of the masses until sufficient cytopathologic material was obtained for diagnosis; and 2. optimal specimen preparation. It is concluded that immediate on-site cytopathological procurement and evaluation of fine needle aspirates of head and neck masses is a valuable practice which assures a higher yield of adequate specimens compared to biopsies taken without immediate evaluation. The technique of immediate on-site evaluation of FNAs is discussed and a cost-benefit analysis of immediate on-site evaluation of FNAs is presented.

Significance of peritoneal washings in gynecologic oncology. The experience with 901 intraoperative washings at an academic medical center.

OBJECTIVE: Peritoneal washings are routinely performed during gynecologic surgery. The presence or absence of malignant cells in washings helps determine the stage of the malignancy. However, the efficacy of this procedure has not been studied recently. DESIGN: All intraoperative washings for gynecologic disease at our hospital from 1992 through 1994 (901 cases) were reviewed. Of these, 380 were gynecologic malignancies that were reviewed for changes in staging based on the presence of malignant cells. RESULTS: Histologically, 380 cases were gynecologic malignancies, 521 benign, 79 nongynecologic, and 25 had no accompanying surgical pathology. Of the malignancies, 125 had a diagnosis of cancer on washings. In 12 cases (3.1%), a change in stage resulted. CONCLUSIONS: In a small but significant number of cases, malignant cells in the washings changed postoperative staging, impacting therapeutic measures and prognosis for these patients greatly. Peritoneal washings remain a simple yet effective tool in the evaluation and management of gynecologic malignancies.

Ectopic cervical thymic tissue: diagnosis by fine needle aspiration.

Cervical thymic masses are congenital lesions that result from aberrant thymic migration during embryogenesis. Although most of these masses are asymptomatic, they may cause debilitating symptoms secondary to encroachment on adjacent aerodigestive structures. Preoperative diagnosis of ectopic thymic tissue is rare; most cases are clinically misinterpreted as branchial cleft remnants or cystic hygromas. Definitive diagnosis has relied on histopathologic examination in nearly all reported cases. However, the invasiveness of open incisional or excisional biopsy carries the risk of surgical and anesthetic complications. Inadvertent surgical thymectomy may result in cell-mediated immune deficiencies in infants and young children. The utility of fine needle aspiration is gaining wider acceptance in the diagnostic evaluation of neck masses. We describe an infant with an asymptomatic cervical thymic mass diagnosed by fine needle aspiration.