Effect of erionite on the pleural mesothelium of the Fischer 344 rat.

OBJECTIVE: This study sought to assess the fibrogenic and carcinogenic potential of erionite (a fibrous zeolite) on the pleural mesothelium of the Fischer 344 rat (n = 24). DESIGN: The study was designed to examine rat pleural mesothelial changes by three independent observers at timed intervals, ranging from 1 to 480 days postinoculation using erionite from the Pine Valley, Nevada (USA) area. The mean length and width of the erionite fibers were 2.29 and 0.48 microns, respectively. Only microscopic observations made by majority (2/3) or unanimity (3/3) were accepted for final diagnosis. RESULTS: Pleural and lung tissue were available for examination in 21 of the 24 rats. Fibrosis, chronic inflammation, and foreign body reaction occurred in 6 of 21 rats. Mesothelial hyperplasia and dysplasia occurred in 9 and 3 of the 21 rats, respectively. A single mesothelioma was identified at 434 days in a rat that had gross nodular pleural lesions. CONCLUSIONS: The findings reported herein confirm the strong fibrogenic potential of erionite but are at variance with previous studies reporting much higher yields of mesothelioma. The reasons for the low yield of mesothelioma in this study are not known, but may be related to the study design, the strict criteria used for histopathologic diagnosis, and/or possible differences in erionite physicochemical properties, associated with its geographic distribution, most previous animal studies having used erionite from the Rome, Oregon (USA) area.

Potential utility of p53 immunopositivity in differentiation of adenocarcinomas from reactive epithelial atypias of the lung.

Reactive atypia of alveolar epithelium occurs in many types of lung injury and may sometimes raise suspicions of adenocarcinoma or bronchioloalveolar carcinoma. To assess whether there is sufficient difference in the frequency of p53 protein immunopositivity in these lesions to provide a practical basis for differentiating malignancy from reactive atypia, we immunostained 110 malignant and inflammatory/fibrotic lung specimens for p53 protein. Paraffin-embedded sections were immunostained with p53 protein antibody (clone BP53-12; BioGenex, San Ramon, CA) and standard capillary gap (Microprobe; Fisher Scientific, Fairlawn, NJ) avidin- biotin complex technique with antigen retrieval solution. Percent of immunopositive cells was semiquantitatively categorized as follows: 0%, less than 1%, 1% to 10%, 10% to 50%, more than 50%. Of reactive atypias, 94% are negative or show p53 immunopositivity in less than 10% of cells. Of p53 positive malignancies, 86% are positive in more than 10% of cells. When p53 immunopositivity occurs in more than 10% of atypical cells, the lesion is usually a malignancy, primarily adenocarcinoma. Most reactive atypias are immunopositive in less than 10% of atypical cells. Important caveats were noted. Rare reactive atypias are p53 immunopositive in greater than 10% of cells. Bronchioloalveolar carcinomas are infrequently p53 immunopositive. Therefore, this approach would be less useful in their differentiation from reactive atypias.

Calcofluor white stain for the detection of Pneumocystis carinii in transbronchial lung biopsy specimens: a study of 68 cases.

Calcofluor white (CFW), a chemofluorescent agent, has proven effective in the recognition of Pneumocystis carinii cysts in respiratory fluids and secretions. However, its usefulness in the recognition of P. carinii cysts in tissue preparations has not been established. We studied 68 formalin-fixed, paraffin-embedded, transbronchial tissue biopsy specimens from individuals seropositive for the human immunodeficiency virus and stained them with the CFW stain and the conventional Gomori methenamine silver (GMS) stain to determine the concordance rate of the two stains. CFW-positive specimens showed light peripheral staining and a unique double parenthesis-like structure near the center of the cysts. Thirty-six (52.9%) of the 68 specimens were CFW and GMS positive, whereas 27 (39.7%) of the specimens were negative by both techniques, yielding a concordance rate of 92.6%. Five (7.4%) of the 68 specimens showed disparate results, and, of these, four (5.9%) were CFW positive and GMS negative, whereas one (1.5%) was CFW negative and GMS positive. We conclude that the CFW stain is suitable and useful for the demonstration of P. carinii cysts in tissue preparations.

Beta-Carotene, vitamin A, and lung cancer chemoprevention: results of an intermediate endpoint study.

A randomized, placebo-controlled clinical trial of beta-carotene and retinol was conducted with 755 former asbestos workers as study subjects. The targeted endpoint for the intervention study was a reduction in the incidence and prevalence of sputum atypia. The dosage of 50 mg beta-carotene/d and 25,000 IU retinol/d on alternate days resulted significant increases in serum concentrations of both agents with no clinically significant toxicity. Skin yellowing was observed in approximately 35% of patients and may have contributed adversely to protocol adherence. Baseline analysis revealed that smoking and drinking were associated with lower concentrations of serum beta-carotene, even after dietary carotene intake was adjusted for (P < 0.0001). Baseline concentrations of retinol were apparently lowered by smoking (P < 0.002) and increased by drinking (P < 0.0001). Drinking and smoking also were significantly related to lower beta-carotene concentrations after supplementation (P < 0.001). No significant reduction in sputum atypia was observed after treatment.

Quantitative image analysis of MIB-1 immunoreactivity. A comparison with flow cytometric assessment of proliferative activity in invasive carcinoma of the breast.

Proliferative activity, especially flow cytometrically determined S-phase fraction, is generally accepted as an important prognostic indicator in carcinoma of the breast. We studied cellular proliferation in 53 breast carcinomas using quantitative image analysis of immunoreactivity to a recently available monoclonal antibody, MIB-1, which is applicable to formalin-fixed, paraffin-embedded tissues. MIB-1 is a murine monoclonal antibody that reacts with the Ki-67 nuclear antigen expressed by proliferating cells in the late G1, and G2/M phases of the cell cycle. These results were compared to flow cytometric determinations of S-phase and S + G2/M phase fractions obtained from corresponding fresh tissue samples. There was a good correlation between quantitative immunoreactivity to MIB-1 as measured by image analysis and flow cytometric S-phase and S + G2/M phase fractions (r = .63, P < .00001; r = .607, P < .00001, respectively). Immunoreactivity to MIB-1 and flow cytometric S-phase and S + G2/M phase fractions were significantly increased in aneuploid tumors as compared to diploid tumors. Histologic grade correlated with flow cytometric S-phase and S + G2/M phase fractions and MIB-1 immunoreactivity as determined by image analysis. There was a correlation between tumor size and MIB immunoreactivity. No proliferative parameters significantly correlated with lymph node status. Assessment of proliferative activity by quantitative image analysis of immunoreactivity to monoclonal MIB-1 antibody may be employed in cases of invasive carcinoma of the breast in which flow cytometric analysis fails to result in quantitative proliferative values, or it may be used as an alternative measurement of such proliferative activity.

Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance).

PURPOSE: To assess the efficacy of chest radiography in the detection of active pulmonary tuberculosis in patients with acquired immunodeficiency syndrome (AIDS). MATERIALS AND METHODS: Initial interpretations of chest radiographs of 133 adult patients with AIDS and positive sputum or bronchoalveolar lavage cultures for Mycobacterium tuberculosis were reviewed. Radiographic findings were correlated with CD4 T-cell counts, sputum stains for acid-fast bacilli (AFB), and antituberculous drug sensitivity. RESULTS: Forty-eight (36%) patients had a primary M tuberculosis pattern, 38 (28%) had a postprimary M tuberculosis pattern, 19 (14%) had normal radiographs, 17 (13%) had atypical infiltrates, seven (5%) had minimal radiographic changes, and four (3%) had a miliary pattern. Normal chest radiographs were seen for 10 (21%) of 48 patients with less than 200 T cells per microliter and one (5%) of 20 patients with more than 200 T cells per microliter. Drug sensitivity and sputum staining for AFB did not correlate with radiographic findings. Overall, 19% of cases had multidrug resistance to antituberculous medications. CONCLUSION: Chest radiographs did not suggest active tuberculosis in 43 (32%) of 133 AIDS patients with active pulmonary tuberculosis.

Effect of fibrous glass on rat pleural mesothelium. Histopathologic observations.

Female Fisher 344 rats (n = 25) were inoculated intrapleurally with a single 20-mg dose of (JM-100) fibrous glass. The mean length (2.2 microns) and width (0.15 microns) of the fibrous glass particles was within respirable range. Following inoculation, the rats were killed at timed intervals ranging from 2 to 430 d from inoculation. The pleural histopathologic changes were independently observed by a panel of three pathologists blinded to the time elapsed from inoculation. Fibrous adhesions, nodular lesions, and grossly evident tumor were noted in 15, 2, and 1 rat, respectively. In 1 rat there were combined adhesive and nodular changes, and in 6 there were no grossly detectable abnormalities. Chronic inflammation, fibrosis, and foreign body reaction were found in 9, 18, and 10 rats, respectively. Mesothelial hyperplasia and dysplasia were observed in 16 and 9 rats, respectively. Of 16 rats with the severest degree of hyperplasia and dysplasia, 3 developed malignant mesothelioma. This study suggests that a spectrum of rat pleural mesothelial histopathologic changes occurs before development of mesothelioma. The association of severe dysplasia in 3 rats with fully developed mesothelioma suggests that there may be a gradual progression from mesothelial hyperplasia or dysplasia to mesothelioma. Multivariate analysis further suggests that gross pleural nodular lesions and dysplasia may be significantly associated with the development of mesothelioma in this experimental model.

Reproducibility of major diagnoses in a binational study of lung cancer in uranium miners and atomic bomb survivors.

A binational panel of four Japanese and four American pathologists examined 208 pulmonary neoplasms, according to the World Health Organization (WHO) recommendations, second edition, for the histologic typing of lung tumors. The study design included independent evaluations by pathologists working alone, followed by group reviews. The individual evaluations, and their implications for reproducibility of the WHO recommendations, are reported. Consensus (agreement by six or more pathologists) with respect to major (ie, first digit) diagnosis was obtained for 76.4% of the cases. Consensus was obtained for 72.5% of the cases with any major diagnosis of small cell cancer; the comparable figures for adenocarcinoma and squamous cell carcinoma were 56% and 48%, respectively. American pathologists were twice as likely as Japanese pathologists to diagnose large-cell cancer, the only significant national difference. Consensus was far less frequent with the minor (ie, second digit) diagnosis categories. This study shows that lung cancers continue to be difficult to classify reproducibly.

Pulmonary histopathology in cocaine abusers.

Lung histopathology was reviewed from 52 autopsies with positive toxicologic tests for cocaine from the medical examiners' offices in Dallas and Austin, TX. The median patient age was 34.7 years, and the male to female ratio was 2:1. Twelve individuals primarily used the drug intravenously and six primarily smoked it, but in most patients usage history was not known. The most frequent manner of death was accidental, consisting predominantly of cocaine overdoses. Other frequent manners of death included both natural causes and homicides. Subjects with chest trauma were excluded from the study. Twenty-three age-matched control cases with negative cocaine histories and toxicologic tests also were obtained from medical examiner autopsies. Histopathologic findings in the cocaine abuse group included acute hemorrhage, 58% (P = .05); chronic hemorrhage, 40% (P < .01), interstitial pneumonitis/fibrosis, 38% (P < 0.01); congestion, 88% (P < .01); and intra-alveolar edema, 77% (P < .01). These changes were remarkably consistent regardless of locale or method of use. Our findings demonstrate that pulmonary hemorrhage is more frequent than suggested by clinical hemoptysis and that chronic pulmonary diseases such as interstitial fibrosis may develop in long-term users.

Lung cancer in the young.

Lung cancer is uncommon in individuals age 40 or less. We reviewed the Cancer Registry files of the Ben Taub General Hospital (Houston, TX) from 1971 to 1989 and identified 1678 patients with a documented diagnosis of lung cancer. Among these 1678 patients, 50 (2.98%) were age 40 or less. Thirty-five (70%) of the 50 patients were men and 15 (30%) were women. Their median age was 37 (range of 24 to 40). A smoking history was available in 37 patients. Thirty-five (94.5%) of the 37 patients who were smokers had a > 20-pack per year history of smoking. Four patients were intravenous drug abusers, and one of these four tested positive for the immunodeficiency virus. Twenty-seven (54%) had adenocarcinoma, eight (16%) had squamous cell carcinoma, and six (12%) had other nondescript, nonsmall-cell carcinoma types. In contrast, the proportion of adenocarcinoma for the (all-age) group of 1678 patients with lung cancer was 28.2%. This difference in the proportion of adenocarcinoma between the two age groups was statistically significant (Pearson's Chi 2, 13.7039, p < 0.0005). Thirty-one (77.5%) of the 50 patients had unresectable disease at diagnosis (12 had stage IIIb and 19 had stage IV). The median survival from diagnosis was 26 weeks. These findings suggest that (1) smoking is an important risk factor for this subset of young patients, (2) the proportion of adenocarcinoma is higher in the young compared with the entire group of lung cancer patients, which included patients of all ages, and (3) young patients tend to present with advanced disease at diagnosis, resulting in an extremely poor survival.

Concurrent mesothelioma and adenocarcinoma of the lung in a patient with asbestosis.

We report the apparently unique simultaneous development of a mesothelioma and an adenocarcinoma of the lung in a patient with asbestosis. Pathologists should be aware that very rarely these two malignancies may occur concurrently, an event with potential prognostic, therapeutic, and medical-legal implications for the patient and his family. Although occupational asbestos exposure is well recognized as a risk factor in the development of both mesothelioma and lung carcinoma, this case report emphasizes the rarity of the synchronous occurrence of these tumors in asbestos exposed individuals suggesting that the mechanism by which asbestos fibers induce lung carcinoma is different from that by which they induce mesothelioma.

Radiation-associated lung cancer: a comparison of the histology of lung cancers in uranium miners and survivors of the atomic bombings of Hiroshima and Nagasaki.

A binational panel of Japanese and American pulmonary pathologists reviewed tissue slides of lung cancer cases diagnosed among Japanese A-bomb survivors and American uranium miners and classified the cases according to histological subtype. Blind reviews were completed on slides from 92 uranium miners and 108 A-bomb survivors, without knowledge of population, sex, age, smoking history, or level of radiation exposure. Consensus diagnoses were obtained with respect to principal subtype, including squamous-cell cancer, small-cell cancer, adenocarcinoma, and less frequent subtypes. The results were analyzed in terms of population, radiation dose, and smoking history. As expected, the proportion of squamous-cell cancer was positively related to smoking history in both populations. The relative frequencies of small-cell cancer and adenocarcinoma were very different in the two populations, but this difference was accounted for adequately by differences in radiation dose or, more specifically, dose-based relative risk estimates based on published data. Radiation-induced cancers appeared more likely to be of the small-cell subtype, and less likely to be adenocarcinomas, in both populations. The data appeared to require no additional explanation in terms of radiation quality (alpha particles vs gamma rays), uniform or local irradiation, inhaled vs external radiation source, or other population difference.

Use of morphometry as an aid in the differential diagnosis of large cell carcinoma of the lung.

In a previous cytopathologic study a regression equation was generated that aided in the differential diagnosis of large cell carcinoma (LCC) of the lung from poorly differentiated adenocarcinoma (AC). This study was undertaken to validate and extend those findings. Cytopathologic and histopathologic specimens from 20 new patients were examined using computerized morphometry. There were 28 specimens from 10 cases of LCC and 25 specimens from 10 cases of AC (10-25 cells measured from each specimen). Histopathologic review by an expert (S.D.G.) provided the "gold standard" diagnosis. Morphometric parameters studied were (1) nucleolar/nuclear area ratio, (2) cell area, (3) cell form factor, and (4) nuclear form factor. Sensitivity analysis validated the diagnostic utility of our prior equation. A logistic regression with these parameters determined the probability that each sample was LCC. Relative operating characteristic curve analysis determined an optimum logistic cutoff point of 0.83. At this decision level the equation had a sensitivity of 72% for distinguishing LCC. Specificity was 46%, positive predictive value was 65%, negative predictive value was 55%, and classification efficiency was 61%. Morphometry of histopathologic material contributed no important additional information. Therefore, our logistic regression and sensitivity analysis supported the clinical utility of certain morphometric measurements in the cytopathologic, but not histopathologic, diagnosis of LCC.

Amiodarone pulmonary toxicity: a multidisciplinary review of current status.

Amiodarone, a benzofuran derivative, has proven useful in the control of serious cardiac arrhythmias. We reviewed the English language medical literature to characterize clinical, radiographic, scintigraphic, pathologic, diagnostic, and prognostic data concerning amiodarone pulmonary toxicity. Our review showed that features consistent with amiodarone pulmonary toxicity include exertional dyspnea, fever, and high sedimentation rates, usually in patients taking larger maintenance doses. Positive findings on gallium scan, foamy alveolar macrophages on lung biopsy or bronchoalveolar lavage, and resolution of abnormal chest roentgenogram upon withdrawal of amiodarone and/or institution of corticosteroid therapy support a diagnosis of amiodarone pulmonary toxicity. Conversely, maintenance doses of 400 mg or less daily, normal lung diffusing capacity and bronchoalveolar lavage or lung biopsy specimens without foamy alveolar macrophages are features that make amiodarone pulmonary toxicity unlikely. Amiodarone pulmonary toxicity should be considered in any patient who has new or clinical worsening of respiratory symptoms and/or abnormalities on chest roentgenogram. Congestive heart failure is often present in these patients and must be excluded before a diagnosis of amiodarone pulmonary toxicity can be considered. Amiodarone pulmonary toxicity also needs to be distinguished from pulmonary infection. Therefore, amiodarone pulmonary toxicity remains a clinical diagnosis relying upon a composite of clinical, radiographic, and histopathologic findings.

Experimental polyacrylamide-induced acute injury in rat lung.

We recently reported the first case of accidental aspiration of polyacrylamide occurring in a 26-year-old man. The patient developed severe airway obstruction and parenchymal lung damage and died. Autopsy revealed numerous polyacrylamide particles in his lungs, as well as extensive bronchiolar and alveolar damage. Gas chromatographic and mass spectrometric assessment of the lung tissue failed to reveal polyacrylamide activity, although assessment of the suspending solvent of the polyacrylamide showed a pattern characteristic of an aliphatic hydrocarbon mixture with a prominent dodecane peak. This experimental study was performed to determine the nature and extent of damage to rat bronchial and alveolar epithelia following endotracheal instillation of polyacrylamide, hydrocarbon mixture (petroleum distillate), dodecane (C12H26), or normal saline. The rat lungs were examined grossly and microscopically 10 min and 24, 72, and 96 h after endotracheal instillation, following inflation and fixation with 10 percent buffered formaldehyde. Gross examination revealed congested, mottled visceral pleural surfaces in the rats treated with polyacrylamide and dodecane. There were no pleural exudates or effusions. Microscopically, vascular engorgement, bronchiolitis, and focal pneumonia were observed. Vascular engorgement was most pronounced at 72 to 96 h in rat lungs treated with polyacrylamide and dodecane and was moderate at 24 h in rats treated with petroleum distillate. Focal organizing pneumonia was marked at 96 h in rats treated with petroleum distillate, at 72 h in those treated with polyacrylamide, and at 24 h in those treated with dodecane. The saline-treated control animals showed no change. Our findings suggest that polyacrylamide, dodecane, and petroleum distillate are strong irritants to the airways. However, a direct obstructive/mechanical effect of the polyacrylamide upon the airway has not been excluded. Airway exposure to polyacrylamide may result in lung injury secondary to the polyacrylamide itself, its suspending agents, or both.

Transbronchial lung biopsy. Histopathologic and morphometric assessment of diagnostic utility.

The diagnostic utility of transbronchial lung biopsy (TBB) is partly a function of its size. However, objective parameters that reflect biopsy specimen size have not yet been well-defined. We studied clinical records and histopathologic lung tissue slides of 116 patients who underwent diagnostic TBB, aiming to define the possible significance of association between seven parameters and three categories of pathologic diagnoses. Three of the seven parameters were clinical: age, sex, and chest roentgenographic infiltrates (localized vs diffuse). The remaining four parameters were histopathologic and morphometric: total number of tissue fragments, total number of alveoli (per biopsy specimen), total tissue area (alveolated plus nonalveolated), and lung total area (alveolated tissue alone). The three categories of pathologic diagnoses were as follows: infection, tumor, and nonspecific diagnoses. The nonspecific diagnoses included diagnoses of fibrosis and/or chronic inflammation. The alveoli were microscopically counted by one of us (S.D.G.). The number of biopsy fragments, the total tissue area, and the total lung area were measured in square millimeters by a computer-assisted digitizing system using specific (Bio-Quant) software (R and M Biometrics Inc). The significance of the associations between the seven parameters and the three diagnostic categories were assessed by the chi2 test for association. Overall, the following four possible associations were found to be statistically significant: (1) age--a lower percentage of patients with infection was found among patients with increasing age (p less than 0.001); (2) roentgenographic findings--a greater percentage of tumor diagnoses were found in patients with localized infiltrates (p = 0.006); (3) number of biopsy fragments--a greater percentage of patients with diagnoses of infection was identified among patients whose biopsy specimens contained the highest number of tissue fragments (p = 0.04); and (4) number of alveoli--a greater percentage of diagnosis of infection was made in patients whose biopsy specimens contained greater than or equal to 20 alveoli (p = 0.01). Our findings support the notion that the diagnostic utility of TBB is related to its size. However, this relationship between TBB size and diagnostic utility was apparent only for diagnoses of infection and not for diagnoses of tumor. We conclude that TBB specimens containing 20 or more alveoli may (1) be declared to be adequate for diagnosis, (2) in the appropriate clinical setting, they will be most likely to yield a diagnosis of infection, and (3) the number of alveoli does not appear to be associated to the diagnosis of tumor.

Morphometric quantitation of tumor necrosis in stage 1 non-small cell carcinoma of lung: prognostic implications.

We objectively examined the extent of tumor necrosis by computer-assisted morphometry in 28 patients with surgically resected Stage I non-small cell carcinoma of lung. Fourteen of the 28 patients were long-term survivors (mean survival after diagnosis 94 mo) and 14 were short-term survivors (up to 62 mo after diagnosis). The extent of tumor necrosis was determined by means of a computer assisted digitizing system. The two sample t test and the two-tailed Wilcoxon rank score tests were used for statistical analysis of comparison of the extent of tumor necrosis between the two groups of patients. This morphometric study showed that the extent of tumor necrosis was significantly associated to the probability of long-term survival, with long surviving patients having a lesser degree of tumor necrosis (t = 2.75, p < 0.02, 2 sample t test, two-tailed, df = 26). These findings reaffirm previous subjective data, derived from pathologist assessment of tumor necrosis, and suggest that morphometric evaluation of tumor necrosis may play a useful adjunct role in predicting prognosis of carcinoma of lung.

Epidemiology of bronchioloalveolar carcinoma.

Descriptive features of bronchioloalveolar carcinoma (BAC) are presented using Surveillance, Epidemiology and End Results Program population-based incidence data from 1973 through 1987, along with risk factors from histologically confirmed cases of BAC identified in a hospital-based case-control study conducted in Louisiana between 1979 and 1982. Compared to the rising incidence of lung cancer overall, BAC rates have remained relatively constant, accounting for less than 3% of all lung cancer. BAC incidence rates were higher in males, yet it explained proportionately more of the total lung cancer incidence in females. In the case-control study, 21 of the 33 cases originally ascertained from hospital pathology records were histologically confirmed as BAC. Most cases smoked cigarettes, with a 4-fold risk for ever smoking. Risks tended to increase with smoking intensity (reaching 10-fold for more than 1.5 packs/day) and duration (reaching 5-fold for more than 45 years of smoking). Following 10 or more years of employment, there was a 4-fold risk associated with motor freight occupations, along with nonsignificant excesses among construction workers, petroleum manufacturers, and sugar cane farmers. Cases were more likely than controls to have had emphysema or to have had a close family member with lung cancer. Although based on small numbers, this study suggests that BAC shares many of the epidemiological characteristics of lung adenocarcinoma.

Absence of correlation between nuclear morphometry and survival in stage I non-small cell lung carcinoma.

To evaluate the utility of nuclear morphometry as a prognostic indicator in lung cancer, 5-year follow-up information was obtained in 46 cases of surgically resected Stage I non-small cell lung cancer (NSCLC). Nuclear area, perimeter, major diameter, minor diameter, and nuclear shape factor were determined from representative histologic sections of the tumors with a computer-assisted digitizing system. The morphometric parameters were compared between patients with favorable outcome (Group I: alive with no evidence of disease, n = 17) and those with poor outcome (Group II: dead of disease or with recurrence of disease, n = 29). No significant differences in any of the morphometric parameters were found between tumors in Groups I and II for individual tumor cell types or the combined cases. Failure to demonstrate a correlation between morphometric parameters and prognosis in Stage I NSCLC indicates that future efforts to determine objective prognostic factors should concentrate on other variables, such as specific genetic abnormalities.

Prognostic significance of histopathologic subtype and stage in small cell lung cancer.

A study of 149 light microscopic tissue slides from 147 patients with recorded initial diagnoses of small cell lung cancer (SCLC) (114 cases) and undifferentiated carcinoma (35 cases) was undertaken to test the reproducibility and prognostic impact of a new histopathologic subclassification of SCLC proposed by the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). This study was further designed to test the impact of clinical stage, age, sex, and race on survival. The tissue slides were blindly reclassified as SCLC or non-SCLC by a panel of five pathologists with no knowledge of the initial diagnosis. The SCLCs were divided into the three subtypes outlined by the IASLC pathology panel: small (classic or pure), mixed (small cell/large cell), and combined (small cell/squamous carcinoma or small cell/adenocarcinoma). Small cell lung cancer was clinically staged as local, regional, or distant. Consensus diagnosis (defined as agreement by at least three of the five pathologists) was achieved in 144 (96.6%) of the 149 cases. Of these 144 cases, 124 were reclassified as SCLC (115 [92.8%] small, five [4.0%] mixed, and four [3.2%] combined) and 20 were classified as non-SCLC. The median lengths of survival for the small, mixed, and combined subtypes were 225, 1,110, and 203 days, respectively (P = .025). Adequate staging data were available in 123 of the 124 SCLC cases. Of the 123 SCLC cases, 27 (21.9%) were local, 22 (17.9%) were regional, and 74 (60.2%) were distant stage. The median lengths of survival for the local, regional, and distant stages were 428, 251, and 111 days, respectively. This association was highly significant (P = .0001). We conclude that stage is the major determinant of survival in SCLC. Mixed subtypes had significantly longer survival times than the small or combined subtypes (P = .025). Survival times were longer for women than for men, and the survival time difference between men and women was significant (P = .0028). We found no significant differences in survival according to age or race.