Studies on Pulmonary Anthracosis With Special Reference to the Mineral Constitution of Intrapulmonary Particulate Pollutants in the Human Lung

In order to investigate anthracosis of the human lung, especially its causal relationship with atmospheric pollution and the occurrence of lung cancer, intrapulmonary particulate pollutants (IPP) from autopsy cases and patients lobectomized because of lung cancer were separated by alkali digestion of the lung tissue, and their elemental constitution was analyzed by a wavelength-dispersive X-ray fluorescence spectrometer. Silicon was the most abundant mineral constituent of non-carbonaceous fraction of IPP, followed by calcium, magnesium, iron, aluminum and other trace elements. The levels of silicon and aluminum in IPP were significantly higher in individuals treated at Saitama Medical School Hospital than in those from Tokyo. Farmers showed higher levels of silicon and aluminum than other occupational categories, whereas male blue-collar workers showed higher levels of calcium and lead than farmers. The level of iron in IPP of male smokers tended to be higher than in non-smokers. In cases of lung cancer, especially of the hilar type, the levels of iron, calcium, copper, lead, chromium and nickel in IPP tended to be higher than in non-lung cancer cases, whereas the levels of silicon and aluminum were lower than in non-lung cancer cases. On the basis of these results, pulmonary anthracosis was considered to be etiologically related to the occurrence of lung cancer. Acta Pathol Jpn 40: 41–49, 1990.     

Early cancer and related lesions in the bronchial epithelium in former workers of mustard gas factory

The bronchial epithelium in stepwise transverse sections was examined histologically in 66 male autopsy cases, composed of the groups of 19 mustard gas (MG) ex-workers with lung cancer, 17 MG ex-workers with non-lung cancer, 10 non-MG lung cancer cases, and 20 non-MG non-lung cancer cases. Foci of moderate or severe atypical cellular lesion or dysplasia, or of carcinoma in situ (CIS) in total slides of each group, were counted as 146 in 3,485, 72 in 2,226, 70 in 3,797, and 18 in 4,611, respectively. The relative frequency of moderate or severe dysplasia and CIS in MG exposed non-lung cancer cases resembled that found in lung cancer cases of both MG and non-MG exposed. Seven CIS lesions were detected from among all MG-exposed cases and one CIS was found in a non-MG lung cancer case. Six out of eight CIS examples were adjoined by dysplasia. A multi-variate analysis revealed a significant correlation between the incidence of atypical lesions and MG exposure, though the incidence of atypical lesions was also influenced significantly by age, smoking, and chronic bronchitis. The incidence of atypical lesions was significantly higher in cases of squamous cell lung cancer than those of other histological types, particularly small cell cancer.     

EARLY CANCER AND RELATED LESIONS IN THE BRONCHIAL EPITHELIUM IN FORMER WORKERS OF MUSTARD GAS FACTORY

The bronchial epithelium in stepwise transverse sections was examined histologically in 66 male autopsy cases, composed of the groups of 19 mustard gas (MG) ex-workers with lung cancer, 17 MG ex-workers with non-lung cancer, 10 non-MG lung cancer cases, and 20 non-MG non-lung cancer cases. Foci of moderate or severe atypical cellular lesion or dysplasia, or of carcinoma in situ (CIS) in total slides of each group, were counted as 146 in 3,485, 72 in 2, 226, 70 in 3,797, and 18 in 4,611, respectively. The relative frequency of moderate or severe dysplasia and CIS in MG exposed non-lung cancer cases resembled that found in lung cancer cases of both MG and non-MG exposed. Seven CIS lesions were detected from among all MG-exposed cases and one CIS was found in a non-MG lung cancer case. Six out of eight CIS examples were adjoined by dysplasia. A multi-variate analysis revealed a significant correlation between the incidence of atypical lesions and MG exposure, though the incidence of atypical lesions was also influenced significantly by age, smoking, and chronic bronchitis. The incidence of atypical lesions was significantly higher in cases of squamous cell lung cancer than those of other histological types, particularly small cell cancer.     

EXTRACTION OF FERRUGINOUS BODIES FROM LUNG TISSUE OBTAINED AT SURGERY and AUTOPSY

Ferruginous bodies were extracted quantitatively from 508 patients; operated 242 with lung cancer and 94 with non-lung cancer, and autopsy 51 from hepatomas, 42 from stomach cancers, and 79 from non-cancer diseases. The bodies were divided morphologically into 4 types; 2 types may be from asbestos and the other 2 types from carbon and silicate which were very rarely found. The incidence of the bodies was the highest in hepatoma 96.8, followed by lung cancer 90.8%, non-lung cancer 80%, stomach cancer 76.2%, and non-cancer 74.2% in the years 1975–1981. Distribution of count of asbestos bodies was characteristic in patients with lung cancer, i.e. the cases who had asbestos bodies above 100/5 g of wet lung were found in 36 of 242 patients with lung cancer (14.8%) who were all smokers and 15 of 266 patients with the other diseases (5.6%) with significant difference between the two groups. Moreover, out of 14 patients who had the bodies above 300/5 g of wet lung, 9 were patients with lung cancer and also smoked heavily, and remaining 5 patients with diseases other than lung cancer consisted of 2 heavy smokers, a moderate and a mild smoker, and a non-smoker. These evidences may suggest the existence of some relation between occurrence of lung cancer and low degree of asbestos exposure with addition of smoking.     

Titanium particles identified by energy-dispersive X-ray microanalysis within the lungs of a painter at autopsy

A 72-year-old male painter, who complained of his "lungs burning" for 2 weeks, died suddenly. Autopsy examination revealed severe coronary atherosclerosis with plaque rupture as the cause of death. Examination of the lungs revealed emphysema, interstitial fibrosis, and multinucleated giant cells with intra- and extracellular brown-black, crystalline, polarizable foreign material. Energy-dispersive X-ray microanalysis showed the material to contain titanium, aluminum, silicon, and iron. An increased incidence of respiratory disease has been reported in professional painters. Titanium is widely used as a pigment in the manufacturing of commercial paints. Cases of pneumoconiosis and alveolar proteinosis have been described in painters in which analysis of lung tissue revealed increased levels of titanium. This case is presented as an example of a rarely reported phenomenon, which may have clinical implications for evaluation and management of lung disease in painters.     

Effects of intratracheal administration of bleomycin or saline in pair-fed and control-fed hamsters on daily food intake and on plasma levels of glucose, cortisol, and insulin, and lung levels of calmodulin, calcium, and collagen

In the present study, the effects of intratracheal administration of bleomycin have been examined on daily food intake and on plasma levels of glucose, cortisol, and insulin, and on lung levels of calmodulin, calcium, and collagen in hamsters. Since bleomycin treatment caused nutritional deficiency leading to loss of body weight, we have included pair-fed and control-fed as control groups in order to rule out the nutritional deficiency-related effects on these measurements. Bleomycin-treated animals showed a dramatic decrease in daily food intake and body weight as compared to control-fed animals. Bleomycin-treated animals were hyperglycemic when compared to nutritionally comparable pair-fed animals and had plasma glucose levels similar to those of control-fed animals. Plasma cortisol levels in bleomycin-treated and pair-fed animals showed a time-dependent increasing trend, whereas plasma insulin levels in both groups tended to decrease. The lung levels of calmodulin and calcium in bleomycin-treated animals were significantly increased when compared with the pair-fed or control-fed group. Bleomycin-treated animals had significantly higher levels of lung collagen than pair-fed or control-fed at 7 and 13 days after treatment. The lung collagen content in pair-fed animals was significantly less than that of control-fed at 13 days. It was concluded that a disturbance in carbohydrate metabolism and increased lung levels of calmodulin and calcium might be somehow involved in fibroproliferative changes of the lung in bleomycin-treated animals.     

Observations on the incidence, aetiology, and pathology of senile osteoporosis

Using previously described methods, lumbar vertebral body slabs were investigated radiologically and histologically from 300 unselected cases coming to necropsy. Calcium estimations were also made on the bones of the first 150 cases. High calcium values were mostly encountered in young adults and the calcium values tended to diminish with age, but a wide range of calcium values was still encountered in older subjects. Radiographic density of bone and calcium content tended to be higher in male than in female bone at all ages. The study showed that in subjects aged 50 years or more bone was osteoporotic in 22·5% of males and in 23·1% of females. This is a higher incidence than has been previously reported, and is the first accurate study to show equality of incidence in the two sexes.     

ANNULATE LAMELLAE IN GASTRIC CARCINOMA

A 72-year-old male painter, who complained of his "lungs burning" for 2 weeks, died suddenly. Autopsy examination revealed severe coronary atherosclerosis with plaque rupture as the cause of death. Examination of the lungs revealed emphysema, interstitial fibrosis, and multinucleated giant cells with intra- and extracellular brown-black, crystalline, polarizable foreign material. Energy-dispersive X-ray microanalysis showed the material to contain titanium, aluminum, silicon, and iron. An increased incidence of respiratory disease has been reported in professional painters. Titanium is widely used as a pigment in the manufacturing of commercial paints. Cases of pneumoconiosis and alveolar proteinosis have been described in painters in which analysis of lung tissue revealed increased levels of titanium. This case is presented as an example of a rarely reported phenomenon, which may have clinical implications for evaluation and management of lung disease in painters.     

A Statistical Analysis of Lung Cancer Registered in the Annual of Pathological Autopsy Cases in Japan between 1958 and 1987, with Special Reference to the Characteristics of Lung Cancer in Japan

Autopsy cases of lung cancer, 41,988 in males and 13,818 in females, consecutively registered between 1958 and 1987, were analysed statistically and compared with other case materials and mortality statistics. Cases of malignant tumor showed a gradual increase, and now comprise 60% of the total male and 55% of the total female autopsy cases. The percentage of lung cancer cases among the total autopsy cases was 9% for males and 5% for females. The percentage of lung cancer cases among total cases of malignant tumor was about 17% for males and 9% for females. Among fatal malignant tumors, gastric cancer and lung cancer showed the highest frequency. The relative incidence of gastric cancer was seen to decrease, whereas that of lung cancer increased. Of the histological types of lung cancer in both sexes, adenocarcinoma was the most frequent, followed by squamous cell carcinoma. During the period studied the peak age of patients with lung cancer shifted from the seventh to eighth decade, and a significant elevation of mean age was demonstrated for all of the major histological types in both sexes. The male: female ratio for all lung cancer cases was 3.0, which was much lower than those for the United States and Europe, but very similar to the ratios of mortality statistics in Japan and other Asian countries. As a result of a previous autopsy study at the University of Tokyo, it was also confirmed that the male: female ratio relative to age in each country reflects very well the histological distribution.     

A statistical analysis of lung cancer registered in the Annual of Pathological Autopsy Cases in Japan between 1958 and 1987, with special reference to the characteristics of lung cancer in Japan

Autopsy cases of lung cancer, 41,988 in males and 13,818 in females, consecutively registered between 1958 and 1987, were analysed statistically and compared with other case materials and mortality statistics. Cases of malignant tumor showed a gradual increase, and now comprise 60% of the total male and 55% of the total female autopsy cases. The percentage of lung cancer cases among the total autopsy cases was 9% for males and 5% for females. The percentage of lung cancer cases among total cases of malignant tumor was about 17% for males and 9% for females. Among fatal malignant tumors, gastric cancer and lung cancer showed the highest frequency. The relative incidence of gastric cancer was seen to decrease, whereas that of lung cancer increased. Of the histological types of lung cancer in both sexes, adenocarcinoma was the most frequent, followed by squamous cell carcinoma. During the period studied the peak age of patients with lung cancer shifted from the seventh to eighth decade, and a significant elevation of mean age was demonstrated for all of the major histological types in both sexes. The male:female ratio for all lung cancer cases was 3.0, which was much lower than those for the United States and Europe, but very similar to the ratios of mortality statistics in Japan and other Asian countries. As a result of a previous autopsy study at the University of Tokyo, it was also confirmed that the male:female ratio relative to age in each country reflects very well the histological distribution.     

An altered lectin binding to mucus glycoprotein in goblet cells of human tracheobronchial epithelium among former mustard-gas workers

Lectins, which are well known to have an ability to bind with specific carbohydrate residues of glycoprotein, have been used to examine cellular changes associated with malignant transformation. For the analysis of mucus glycoprotein of goblet cells in the tracheobronchial epithelium, 192 paraffin-embedded sections from 54 autopsy cases including the cases with a history of mustard-gas (MG) exposure were stained with seven plant lectins using PAP method. PNA binding with no neuraminidase treatment as well as BSA-1 binding was observed most frequently in MG-exposed lung cancer cases. The proportion of cases positive for SBA binding in MG-exposed and/or lung cancer cases had a statistical difference from non-MG-exposed non-lung cancer cases. These observations may indicate a large heterogeneity in oligosaccharide chains of mucus glycoprotein and suggest its incomplete or abnormal synthesis, which is most likely to be due to previous exposure to carcinogen, such as MG.     

Chromosomal abnormalities in bronchial epithelium from smokers, nonsmokers, and lung cancer patients

The identification of individuals who are at greatest risk of developing lung cancer would greatly improve diagnosis and possibly lead to early treatment. To study the use of karyotypes for this purpose, we used short-term human bronchial epithelial (hBE) cell cultures from nonsmokers, smokers, and lung cancer patients. Twenty-five metaphases were scored for hBE cell cultures obtained from 32 patients: 8 were nonsmokers, and 24 had a history of smoking (of whom 11 had had lung cancer surgery). The number of abnormal metaphases ranged from 0 to 4 per cell culture. No overall differences in the number of abnormal metaphases were observed between nonsmokers and smokers or between lung cancer patients and non-lung cancer patients. The most commonly observed abnormalities were structural changes in chromosome 1 (six cultures), loss of chromosome 17 (six cultures), and trisomy of chromosome 20 (three cultures). These specific alterations were found almost exclusively in patients with a history of tobacco smoking. The results did not indicate that general chromosomal abnormalities are a useful marker for tobacco smoke exposure or cancer risk.     

AN ALTERED LECTIN BINDING TO MUCUS GLYCOPROTEIN IN GOBLET CELLS OF HUMAN TRACHEOBRONCHIAL EPITHELIUM AMONG FORMER MUSTARD-GAS WORKERS

Lectins, which are well known to have an ability to bind with specific carbohydrate residues of glycoprotein, have been used to examine cellular changes associated with malignant transformation. For the analysis of mucus glycoprotein of goblet cells in the tracheobronchial epithelium, 192 paraffin-embedded sections from 54 autopsy cases including the cases with a history of mustard-gas (MG) exposure were stained with seven plant lectins using PAP method. PNA binding with no neuraminidase treatment as well as BSA-1 binding was observed most frequently in MG-exposed lung cancer cases. The proportion of cases positive for SBA binding in MG-exposed and/or lung cancer cases had a statistical difference from non-MG-exposed non-lung cancer cases. These observations may indicate a large heterogeneity in oligosaccharide chains of mucus glycoprotein and suggest its incomplete or abnormal synthesis, which is most likely to be due to previous exposure to carcinogen, such as MG. ACTA PATHOL. JPN. 37:537–548, 1987.     

Diffuse interstitial pulmonary fibrosis and lung cancer

Forty-two cases of lung cancer complicated with diffuse interstitial pulmonary fibrosis (DIPF) were selected from 13,056 autopsy cases. They were divided into primary (Group I and II) and secondary (Group III) DIPF, and histopathologic and clinicopathologic studies were made. The prevalence of lung cancer with primary DIPF was 17% (8/47) which was significantly (p less than 0.01) higher than that without DIPF (7% or 886/13,009). All eight cases of lung cancer in Group I and II were male, and 7 had cigarette-smoking history. The anatomical sites of lung cancer and DIPF were all peripheral in origin, and in 7 cases located primarily in the lower lobes (left:right = 6:1). Adenocarcinoma was the most common type. The study suggests that male DIPF patients with long clinical history should be followed thoroughly for lung cancer.     

Errors and biases in the diagnosis of cancer of the lung and their influence on risk estimates

When diagnosed as primary lung cancer, metastases from the abdomen, plus false negative cases have little effect on epidemiology studies of male smokers, but may result in a severe dilution of the lung cancers among women and nonsmokers. We have attempted to quantitate this handicap for epidemiological studies using two approaches. The relative frequency of diagnosed primary lung and abdominal cancer among males, women, and nonsmokers differs substantially and is used here to calculate magnitude. The second approach postulates that the ratio of nonsmokers among persons with squamous cell lung cancer and primary adenocarcinoma of the lung would be constant by sex if there were no distortion by abdominal metastases. These two approaches indicate that the much higher ratio of metastatic disease diagnosed as primary lung cancer among nonsmoking women (factor of 15 to 20), makes it more difficult to identify an environmental carcinogen among women or nonsmokers than among male smokers in case-control studies.     

A Moloney Murine Leukemia Virus Driven by the Jaagsiekte Sheep Retrovirus Enhancers Shows Enhanced Specificity for Infectivity in Lung Epithelial Cells

Jaagsiekte sheep retrovirus (JSRV) is the etiologic agent of ovine pulmonary adenocarcinoma (OPA), a transmissible lung cancer in sheep. One of the unique features of this virus is that in infected animals, the only tissues that show expression of the virus are the tumor cells in the lung. We previously showed that the JSRV long terminal repeat (LTR) is preferentially active in murine lung epithelial cell lines (MLE-15 and mtCC1-2). To further explore the tissue specificity, we inserted the JSRV enhancer sequences from the U3 region of the LTR into a Moloney murine leukemia virus (M-MuLV) LTR lacking its own enhancer sequences, to give the chimeric LTR ΔMo + JS. Transient transfection assays indicated that the ΔMo + JS LTR is > 5-fold more active in lung epithelial cell lines than in non-lung lines, compared to the wild-type M-MuLV LTR. This was due to preferential activity of the JSRV enhancers in lung epithelial cells. Moreover, M-MuLV driven by the ΔMo + JS LTR was > 3 logs more infectious in MLE-15 cells compared to non-lung cell lines. This chimeric virus may facilitate investigations of the tissue-specificity of JSRV.     

DIFFUSE INTERSTITIAL PULMONARY FIBROSIS AND LUNG CANCER

Forty-two cases of lung cancer complicated with diffuse interstitial pulmonary fibrosis (DIPF) were selected from 13,056 autopsy cases. They were divided into primary (Group I and II) and secondary (Group III) DIPF, and histopathologic and clinicopathologic studies were made. The prevalence of lung cancer with primary DIPF was 17% (8/47) which was significantly (p< 0.01) higher than that without DIPF (7% or 886/13,009). All eight cases of lung cancer in Group I and II were male, and 7 had cigarette-smoking history. The anatomical sites of lung cancer and DIPF were all peripheral in origin, and in 7 cases located primarily in the lower lobes (left: right = 6: 1). Adenocar-cinoma was the most common type. The study suggests that male DIPF patients with long clinical history should be followed thoroughly for lung cancer.     

Inhalation of inorganic particles as a risk factor for idiopathic pulmonary fibrosis--elemental microanalysis of pulmonary lymph nodes obtained at autopsy cases

Exposure to inorganic particles may induce fibrosis in the lung. However, the association between exposure to inorganic particles and the pathogenesis of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is obscure. We examined inorganic particles in the pulmonary hilar lymph nodes affected by IPF/UIP to investigate whether inhaled elements are involved in the etiology, and whether there is an increasing risk of developing IPF/UIP. Twenty-three IPF/UIP cases and 23 controls without IPF/UIP were investigated. Pulmonary hilar lymph nodes constituted the study material. The elemental analysis was performed using scanning electron microscopy with an energy dispersive X-ray spectroscope, and we analyzed particles quantitatively and qualitatively. The results showed that the cases contained silicon and aluminum as compared with the control in lymph nodes, and these deposits were statistically significantly associated with an increased risk of IPF/UIP (adjusted odds were 2.99, 95% CI: 1.29-6.85 and 57.84, 95% CI: 1.45-2306.19, respectively). In addition, higher nickel levels in lymph nodes were associated with lung cancer. This study shows that inorganic particles, such as Si and Al, have higher concentrations in the hilar lymph nodes in IPF/UIP, and may play a role in one of the risk factors in the pathogenesis of IPF/UIP.     

细胞代谢解毒酶CYP1A1、GSTM1基因多态性与吸烟对男性肺鳞癌发病的影响

 目的 探讨细胞代谢解毒酶细胞色素P450酶1A1（CYP1A1）、谷胱甘肽S-转硫酶M1（GSTM1）基因多态性和吸烟因素对男性肺鳞癌发病的影响。方法 采用基因芯片技术对125例男性肺鳞癌患者和125例男性健康对照者CYP1A1、GSTM1基因多态性进行检测。结果 CYP1A1 m2位点GG基因型和GSTM1缺失基因型在肺鳞癌组与健康对照者间存在显著性差异(P<0.05 )。吸烟者携带CYP1A1 m2位点至少一个变异G等位基因或携带GSTM1缺失型者患肺鳞癌的危险性进一步显著增加,OR值分别为4.50和3.81(P<0.01)。结论 吸烟与CYP1A1、GSTM1基因多态性与男性肺鳞癌的发生有关。     

Relationships of lead, copper, zinc, and cadmium levels versus hematopoiesis and iron parameters in healthy adolescents

To investigate the relationships of trace element concentrations vs hematopoiesis and iron parameters, we measured lead, copper, zinc, cadmium, and ferritin levels in 251 healthy adolescents. Concentrations of trace metals were determined by atomic absorption spectrophotometry. There were no significant gender-related differences in serum copper or serum cadmium concentrations. However, blood lead and serum zinc levels were significantly higher in males than females (3.82+/- 1.24 and 118.4 +/- 43.7 microg/dl vs 2.86+/- 1.06 and 83.5+/- 35.2 microg/dl, p<0.05, respectively). Subjects with elevated lead and copper concentrations exhibited significantly higher leukocyte counts and significantly lower serum iron levels than those with decreased lead and copper concentrations, but no significant differences were observed in blood erythrocyte counts or hemoglobin levels between the 2 groups. Blood lead concentrations were 2-fold higher in male adolescents with leukocytes >9.1 x 10(3)/microl than in those with leukocytes <4.3 x 10(3)/microl (5.04+/- 1.67 microg/dl vs 2.51+/- 0.75 microg/dl, p<0.05). Leukocyte counts had significant correlations with blood lead (r=0.39, p<0.05) and serum copper (r=0.26, p<0.05) in males and zinc (r=0.28, p <0.05) in females. Serum iron levels were inversely correlated with blood lead and serum copper concentrations but were not correlated with serum zinc or cadmium levels. In short, blood lead and serum copper concentrations have important relationships to leukocyte counts and iron parameters in adolescents.