Hajime Kitamura

Primary signet-ring cell carcinoma of the lung: Histochemical and immunohistochemical characterization

To establish criteria for differential diagnosis and to clarify the histogenesis of primary signet-ring cell carcinoma (SRCC) of the lung, five cases were studied by mucin-histochemical and immunohistochemical analyses and compared with SRCC of the gastrointestinal tract and mucus-producing adenocarcinoma of the lung. The proportion of signet-ring cell component varied from 10% to 90% in four cases, and the remaining tumor was a pure SRCC. Mucin-histochemistry showed a close similarity between lung SRCC and goblet cell-type or bronchial gland cell-type adenocarcinoma of the lung. Eighty percent of SRCCs showed positive immunoreactions for lactoferrin, a marker of bronchial gland cell differentiation, the results being consistent with the conclusions in previous studies that lung SRCC is closely related to bronchial gland cell-type adenocarcinoma. The incidence of K-ras mutation detected by the restriction fragment length polymorphism method was relatively high in lung SRCC (three of five) and goblet cell-type adenocarcinoma of the lung (four of four). Mucin-histochemistry indicated that lung SRCC has mucin production similar to that of the colon and colorectal-type SRCCs of the stomach but not to that of gastroduodenal-type SRCC of the stomach. Immunohistochemical staining for MUC-1 and MUC-2 glycoproteins showed a distinct difference; lung SRCC was positive for MUC-1 but negative for MUC-2, whereas colon SRCC and colorectal-type gastric SRCC were negative for MUC-1 but positive for MUC-2.Thus, by a combination of mucin-histochemistry and MUC-1 and MUC-2 immunohistochemistry, primary lung SRCC can be distinguished from metastatic lung SRCC originating in the gastrointestinal tract.

CEMENTED TUNGSTEN CARBIDE PNEUMOCONIOSIS

An autopsy case of cemented tungsten carbide pneumoconiosis, the first lethal case in our country, is presented. A 28‐year‐old woman, who had been engaged in grinding presintered metallic matrix for four years, developed respiratory symptoms. X‐ray examinations were indicative of interstitial pulmonary fibrosis. Corticosteroid therapy revealed only little effect. She expired five years after the onset of the symptoms. Postmortem examination showed nonspecific interstitial pneumonitis resulting in marked lung fibrosis. Ultrastructurally, crystals were observed in cytoplasm of presumable macrophages in the fibrotic lung tissue. Electron probe microanalysis of the lung tissue showed the presence of tungsten and other constituents of tungsten carbide except for cobalt. Metal analysis demonstrated a large amount of tungsten in the lung. Cobalt was detected tenfold of the normal value in the bone. In pathogenesis of the pneumoconiosis in the cemented tungsten carbide workers, toxicity of cobalt is most suspectable, and in addition, individual susceptibility may be also important.

Comparative effects of isosorbide dinitrate, prednisolone, indomethacin, and elastase on the development of monocrotaline-induced pulmonary hypertension.

The pathogenesis of monocrotaline-induced pulmonary hypertension is not clear. Progressive pulmonary arteritis leading to vascular sclerosis, narrowing of the lumina, and thrombosis is the suspected sequence. To investigate this, we examined the effect of isosorbide dinitrate (ISDN), prednisolone, indomethacin, and elastase in 100 SD male rats, 4 weeks after the injection of monocrotaline (MCT) by cardiac catheterization, right ventricle-to-left ventricle plus septum weight ratio (RV/LV + S), histology, and electron microscopy. ISDN, a vasodilator, reduced the elevation of right ventricular (RV) pressure, RV/LV + S, and also pulmonary vascular remodeling; the characteristic histological feature was dilatation of small pulmonary arteries. Both prednisolone and indomethacin reduced RV pressure, RV/LV + S, and pulmonary vasculitis. Elastase, a protease which controls the metabolism of elastin in the arterial wall, likewise reduced RV pressure, RV/LV + S, and pulmonary vascular remodeling, with a significant decrease in elastosis of the small pulmonary arteries histologically. We concluded that all of the pathological processes resulting from arteritis are important in the development of MCT-induced pulmonary hypertension. In all experimental groups, decreased histopathologic changes correlated with decrease in the pressure. Elastase, which reduces pulmonary arterial sclerosis, is suggested as a new agent to treat pulmonary hypertension.

Production of bronchial papilloma with calcitonin-like immunoreactivity in rats exposed to urban ambient air

In order to assess the effect of prolonged inhalation of polluted ambient air on the respiratory tract, 30 Sprague-Dawley rats were kept in facilities built close to a street with heavy traffic in the City of Yokohama for 18 months in an atmosphere of either filtered (filtered group) or non-filtered polluted ambient air (exposed group), and the histology of the lung was examined. Scattered areas of chronic inflammation were seen from the nasal to bronchiolar mucosae in both the groups. Rats which inhaled the urban ambient air showed deposition of dust particles in the alveolar space and the peribronchiolar tissue, but no deposition was recognized in the filtered group. In both the filtered and exposed groups, papillary hyperplasia showing a positive immunoreaction to calcitonin was noted in the bronchobronchiolar epithelium. The hyperplasia was thus shown to have endocrine differentiation and this was considered to be pulmonary endocrine cell hyperplasia. In the exposed group, 2 bronchial papillomas were induced, and were shown to contain cells giving a positive immunoreaction to calcitonin. A histogenetical sequence was suggested in these 2 lesions because of their histological and immunohistochemical similarities.

Modulation of the expression of the Cip/Kip family of cyclin‐dependent kinase inhibitors in foetal developing lungs of hamsters

We examine the cell proliferation activity and expression of cyclin‐dependent kinase inhibitors of the Cip/Kip family, p21Cip1, p27Kip1 and p57Kip2, in foetal hamster lungs to determine the expression patterns of the cyclin‐dependent kinase inhibitors and to clarify the relationship between expression of the cyclin‐dependent kinase inhibitors and lung development. Foetal hamster lungs on gestational days 12.5–16 (the day of birth) and adult lungs were fixed in 4% paraformaldehyde. Frozen sections were immunostained for the cyclin‐dependent kinase inhibitors, and examined by immunostaining for Ki‐67 and bromodeoxyuridine to determine the proliferation activity of the foetal lungs. During the foetal period, cell proliferation activity, as analysed by Ki‐67 or bromodeoxyuridine labelling, decreased with development of the lung. In contrast to the gradual decrease of cell proliferation activity, cells with p27Kip1 immunoreactivity increased with development. On the other hand, p21Cip1‐positive cells were most prominent around gestational day 14.5, while after birth positive cells decreased markedly. A few p57Kip2‐positive cells were detected in the bronchiolar epithelium on gestational day 14.5. Western blotting analyses confirmed these immunostaining patterns. Thus, the levels of the cyclin‐dependent kinase inhibitors of the Cip/Kip family are modulated in the lungs during the foetal period, and each shows a unique expression pattern. The cyclin‐dependent kinase inhibitors may play roles not only in regulating cell proliferation activity but also in regulating other functions such as differentiation in the lung during the foetal period.

Müllerian carcinofibroma of the uterus. A case report.

BACKGROUND Müllerian carcinofibroma is composed of malignant epithelial tumor (cancer) and benign mesenchymal tumors. It is the least frequent among mixed müllerian tumors. There are eight reported cases of carcinofibroma or cases showing similar histology, with only two of these cases recurrent. CASE A case of müllerian carcinofibroma arose in the uterine body. The patient was an 83-year-old, postmenopausal female whose endometrial cytology revealed cell clusters of adenocarcinoma and scattered nonepithelial cells with enlarged nuclei without nuclear atypism or mitosis. Histology of the resected uterus showed a mixture of well to poorly differentiated adenocarcinoma, and fibromatous and leiomyomatous nonepithelial tumors without a transition between them. There was no sign of recurrence nine months after hysterectomy. CONCLUSION Müllerian carcinofibroma seems to have a better prognosis than malignant mixed müllerian tumor. When both cancer cells and an abundance of nonepithelial cells are seen on gynecologic cytology, it may be important to consider mixed müllerian tumor and to differentiate müllerian carcinofibroma from malignant mixed Müllerian tumor by careful observation of the nuclear size, nucleoli, nuclear atypism and mitosis of the nonepithelial cells.

Combined epidermoid and adenocarcinoma in diffuse interstitial pulmonary fibrosis.

This report documents a case of combined epidermoid and adenocarcinoma with idiopathic diffuse interstitial fibrosis developing in the lung. This type of carcinoma with diffuse interstitial fibrosis occurs only rarely in the lungs, in contrast to such carcinoma without fibrosis, which occurs less rarely. A 79-year-old man died of respiratory insufficiency three years after the was diagnosed as having diffuse interstitial pulmonary fibrosis. Six months prior to his death. a tumor shadow was noticed on a radiograph of his chest. Postmortem examination revealed diffuse interstitial pulmonary fibrosis and a primary lung tumor situated peripherally in the right lower lobe. The histologic features of the tumor closely resembled those of mucoepidermoid carcinoma of the major bronchi. However, the tumor had no relation to any bronchi or bronchial glands, and it was evident that no relation to any bronchi or bronchial glands, and it was evident that it had originated from the surface epithelium of the abnormally altered distal airspaces of the honeycomb lung. It is suggested that the malignantly transformed cells originally possessed the potential for bidirectional differentiation to epidermoid and mucous cells.

Modulation of the incidence of hamster pulmonary endocrine cell hyperplasia by unilateral collapse of the lung

We evaluated the effects of the unilateral collapse of the left lung on the formation of pulmonary endocrine cell hyperplasia (PECH) induced by 4-nitroquinoline 1-oxide (4NQO) in Syrian golden hamsters. Ten hamsters were injected subcutaneously with 20 mg/kg body weight of 4NQO, once a week for 4 weeks and treated with injection of silicone rubber into the left thorax at the 8th experimental week. Another 30 animals were divided into three groups: treated with 4NQO only, left lung collapse only, and vehicle only. All animals were sacrificed at the 30th week. The lung tissues were embedded in paraffin; 50 serial sections were made from the tissues of each animal and were studied histologically and immunohistochemically. PECH showed a positive immunostain for calcitonin and/or serotonin. In the uncollapsed right lungs of the animals treated with both 4NQO and unilateral collapse, the mean incidence of PECH was 12.2 x 10(-2)/mm3 lung volume; the incidences of PECH in the animals treated with 4NQO only, collapse only, and vehicle only were 4.1, 3.8, and 1.4 x 10(-2)/mm3, respectively. In the collapsed left lungs, PECH did not form, regardless of 4NQO treatment. This study demonstrates that unilateral collapse of the lung modulates the incidence of PECH induced by 4NQO in hamsters.

Effects of vitamin A on proliferation of human distal airway epithelial cells in culture

Using a serum-free culture method, we investigated the effects of vitamin A on the proliferation of human distal airway epithelial cells. Outgrowth of epithelial cells from lung tissue explants was enhanced by treatment with all-trans retinol at concentrations of 10−8 to 10−7 M. The colony-forming activity of cells harvested from the primary culture and replated onto Swiss 3T3 fibroblastic feeders was, in contrast, significantly reduced by 10−7 M to 10−5 M retinol. When the primary cells were harvested and subcultured on Primaria plates, population expansion was also inhibited by retinol at 10−10 to 10−6 M. We further investigated the cells to determine whether there was any difference in sensitivity to the growth-inhibitory effects of vitamin A between cells from the primary culture incubated with and without retinol. The population increase in cells harvested from the primary culture was inhibited equally in retinol-treated and non-treated cells by subsequent treatment with retinol or retinoic acid, this inhibition being dose-dependent. DNA synthetic activity was also inhibited. Interestingly, both the growth rate and the colony-forming efficiency on feeders were greater in the subculture of cells from the retinol-treated primary culture than in those non-treated. When the cells in the secondary subculture were treated with retinoic acid and replated again, they showed a greater population increase rate than those non-treated. Our results showed that human distal airway epithelial cells isolated from lung tissue were sensitive to the growth-inhibitory effect of vitamin A, but the proliferative potential in some fraction of the epithelial cell population was possibly enhanced by vitamin A treatment.