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A 42-yr-old woman was referred to our hospital because of multiple small nodules in a chest radiograph. She had no symptoms such as dyspnea, cough or sputum. A chest CT revealed many centrilobular small nodules and thin-walled cysts with predominance in the peripheral area of the lungs. The specimens obtained by thoracoscopic surgery showed granulomas with scattered eosinophils and numerous Langerhans' cells. The Langerhans' cells were positive for both S-100 protein and CD1a. These findings are compatible with pulmonary Langerhans' cell histiocytosis (LCH). Since the granulomas showed no fibrotic changes, the LCH may have been in its early stages. However, there were clusters of lymphocytes and macrophages around the terminal and respiratory bronchioles, and cystic lesions without cellular infiltrates, in the specimens. The former histologic findings suggested respiratory bronchiolitis causing interstitial lung disease and the latter are indistinguishable from centrilobular emphysema. Therefore, these smoking-related diseases may have been superimposed on the LCH in this patient.

Although cigarette smoking is a recognized cause of acute eosinophilic pneumonia (AEP), and an increase in eosinophils in the lung is a common occurrence in AEP, early-phase neutrophilia in AEP is not well understood. We describe three cases of cigarette smoke (menthol type)-induced AEP with neutrophilia in the lungs or blood. Increased in-vitro production of the neutrophil chemoattractant interleukin (IL)-8 by human bronchial epithelial cells (HBECs) was correlated with neutrophilia. We suggest that IL-8 released from HBECs is involved in neutrophilia in the lung in AEP, and is newly recognized as an important factor in the early phase of AEP development.

Carbonic anhydrase-related protein (CA-RP) VIII, which is a member of the CA gene family, has been shown to have no catalytic CA activity and its biological function is still unknown. Recently, overexpression of CAs IX and XII has been reported in certain types of malignancy. To investigate a potential role for CA-RP VIII in human colorectal epithelial carcinogenesis, colorectal tissue specimens from surgically resected adenocarcinomas (n = 60) and endoscopically polypectomized adenomas (n = 13) were analysed by immunohistochemistry using monoclonal antibodies to CA-RP VIII and Ki-67 antigen. Less than 5% of epithelial cells in normal colonic mucosae (n = 73) were CA-RP VIII-positive and these were localized to the deep part of the cryptal epithelium. Increased expression of CA-RP VIII was observed in 78% of colorectal carcinomas. An intense signal was frequently observed at the tumour invasion front and its distribution was completely different from that of Ki-67 antigen. Colorectal adenomas also showed significant immunopositivity for CA-RP VIII, but its expression level was much lower than in adenocarcinomas. These findings suggest that CA-RP VIII plays a role in the process of invasion in colorectal cancer., (Copyright 2003 John Wiley & Sons, Ltd.)

It has been argued whether bronchiectasis is truly caused by MAC infection or just a predisposed condition in which MAC colonizes. Our present study was designed to evaluate the pathological findings of bronchiectases caused by Mycobacterium avium intracellulare complex (MAC) lung infection and to demonstrate MAC in the lesion of bronchiectases. A retrospective study was performed in nine cases with positive cultures for MAC in whom lung resections were performed. A determination of whether or not MAC caused pulmonary disease was made using the 1997 criteria required by the American Thoracic Society. In addition, MAC were cultured from all nine lung specimens. Pathological findings of bronchiectases were evaluated in these nine patients. Destruction of bronchial cartilage and smooth muscles layer, obstruction of airway by granulomas, and ulceration of bronchial mucosa were frequently observed. Our present study demonstrates that destruction of fundamental bronchial structure due to extensive granuloma formation throughout the airways was likely the main cause of bronchiectases in MAC infection.

Nonspecific interstitial pneumonia (NSIP) has been recognized as a separate histological classification of interstitial lung disease. Similar features are found not only in idiopathic NSIP, but also in NSIP associated with collagen vascular disorder (CVD-NSIP). We examined the clinical symptoms, laboratory findings, and prognosis of 13 cases of idiopathic NSIP and 11 cases of CVD-NSIP. Immunohistochemical staining was performed using the streptavidin/biotin/peroxidase method with anti-alpha-smooth muscle actin antibody. No differences in the distribution of clinical features, laboratory findings, and prognosis were observed between idiopathic NSIP and CVD-NSIP. In immunohistochemical staining of the fibrosing areas, myofibroblasts were observed in 7 of 13 idiopathic NSIP cases, but in 10 of 11 CVD-NSIP cases. With regards to intra-alveolar organization, myofibroblasts were observed in all 10 CVD-NSIP cases, but they were observed in only 2 of 9 idiopathic NSIP cases. We found a significantly higher myofibroblast proliferation in the intra-alveolar organization of CVD-NSIP compared to idiopathic NSIP. Clinically, idiopathic NSIP and CVD-NSIP are similar, but are pathologically different.

In a previous study, we demonstrated anti-vimentin antibodies in sera of patients with interstitial pneumonia. We hypothesized that antibodies in sera might detect vimentin fragments formed during the process of apoptosis. To prove this, recombinant human vimentin was digested by recombinant human caspase-3 or caspase-8. Then, Western blotting using several commercially available antibodies against human vimentin or patients' sera which had anti-vimentin autoantibodies, was performed. As a result, after recombinant human vimentin was digested by caspase-3 or caspase-8, several vimentin fragments were formed and detected by 2 kinds of monoclonal anti-vimentin antibodies (clone 3B4 and clone V9) as well as by polyclonal sheep anti-human vimentin antibody. It was demonstrated that high molecular weight vimentin was formed after the digestion of vimentin by caspase-3, which was only detected by patients' sera. The high molecular weight vimentin was not formed after digestion of vimentin by caspase-8. Our present results show that high molecular weight vimentin was formed after the digestion of vimentin by caspase-3. In addition, it is suggested that this high molecular weight vimentin acted as an autoantigen to form anti-vimentin autoantibody in vivo.

Salivary gland-type mixed tumor primarily arising in the lung is extremely rare. We report here a case of this type of tumor that occurred in the periphery of S4 of the right middle lobe in a 74-year-old man. Light-microscopically, this lung tumor, 15x9mm in size, exhibited almost the same features as those of mixed tumor of the salivary gland intermingled with chondromyxoid stroma, glandular component, solid growth pattern of myoepithelial components and well-developed cartilage formation, exhibiting a sharp margin. Immunohistochemical study revealed that the glandular components in the tumor was positive for thyroid transcription factor-1, TTF-1, a marker of epithelial cells of the thyroid as well as the lung. Furthermore, surface lining cells of the glandular components and luminal contents were positive for surfactant apoprotein A, PE-10, used as a marker of type II alveolar epithelial cells. These findings clearly demonstrate for the first time that glandular epithelial cells in the present salivary gland-type mixed tumor exhibited differentiation toward type II alveolar epithelial cells.

T-cadherin appears to act as a tumor-suppressor factor in various cancers. Downregulation of T-cadherin is caused by a combination of allelic loss and hypermethylation of the T-cadherin promoter region and is related to cancer invasion. To elucidate the molecular mechanism of invasiveness of basal cell carcinoma of the skin, T-cadherin expression was investigated in archival pathological tissue sections made up of normal counterparts of skin and various types of basal cell carcinoma. Immunohistochemical staining showed that T-cadherin was not expressed in 38 of 51 (75%) basal cell carcinoma specimens, whereas normal counterparts of the skin appeared to express abundant T-cadherin. Loss of heterozygosity in intron 1 of the T-cadherin gene was found in four of 20 informative cases that did not express T-cadherin. Aberrant methylation of the T-cadherin promoter region also was found in six of 25 basal cell carcinomas by methylation-specific polymerase chain reaction. In contrast, no structural alternations were found in two loss of heterozygosity-positive basal cell carcinomas on sequence analysis. These findings indicated that T-cadherin expression was downregulated by a combination of allelic loss and aberrant methylation in basal cell carcinoma of the skin. Loss of T-cadherin expression might be related to the biological behavior of basal cell carcinoma. In addition, results of the present study suggested that downregulation of T-cadherin in various cancers might be related to tumor invasiveness rather than metastasis, because basal cell carcinoma of the skin principally lacks metastatic activity., (Copyright 2002 Wiley-Liss, Inc.)

It has been suggested that lung cancer sometimes aggregates in families. However, the familial occurrence of bronchioloalveolar carcinoma (BAC) is extremely rare. We present a family in which two brothers had BAC. The clinical features and immunohistochemical findings of BAC in the two brothers were compared. Immunohistochemical findings revealed that both cases of BAC had very similar immunopathological features in epithelial marker expression. A review of the literature revealed that this is the third case of BACs in a single family.

Smoking causes various changes in the lung. This report describes a case of cigarette smoke-induced acute eosinophilic pneumonia (CS-AEP) with neutrophilia in the blood. However, the precise mechanism is unknown, so we examined the effect of exposure to cigarette smoke extracts on the production of interleukin (IL)-4, IL-5, IL-8, IL-18, granulocyte macrophage-colony stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) by human bronchial epithelial cells (HBECs) obtained from the patient. We found that IL-8 released from HBECs was involved in neutrophilia in the blood, and is a new factor in the development of AEP, especially in the early phase.

Nonspecific interstitial pneumonia/fibrosis (NSIP) was first described by Katzenstein and Fiorelli in 1994 (Am J Surg Pathol 18: 136-147). Many reports have described that corticosteroids are effective for NSIP. We describe a case of group II idiopathic NSIP in whom cyclophosphamide was administered since the initial response to corticosteroids had been insufficient. Lung biopsy was performed by video-assisted thoracoscopic surgery and NSIP was diagnosed pathologically, clinically and radiologically. Although the initial response to corticosteroids was insufficient, interstitial infiltrates on chest computed tomography improved dramatically after adding intravenous cyclophosphamide followed by oral cyclophosphamide. This case demonstrates that the addition of cyclophosphamide to corticosteroids might be a useful treatment for patients with NSIP.

A 66-year-old woman presented with a progressive myopathy affecting the proximal limbs and unusual pathological findings of nemaline bodies on muscle biopsy. Histological examination demonstrated that the bodies were mainly located in the subsarcolemmal region of atrophic fibers, exhibited strong immunoreactivity with antibodies to both alpha-actinin and m-actin, and had a typical lattice-like appearance at higher magnification on electron microscopy. These findings were the same as those for nemaline myopathy. The patient responded to steroid therapy, but relapse occurred after steroid was discontinued. Given the clinical criteria of polymyositis, we believe that the occurrence of nemaline bodies in our patient should be interpreted primarily as an epiphenomenon of primary myopathy.

Objective: The present study was designed to evaluate the process of cavity formation in Mycobacterium avium intracellulare complex (MAC) lung infection, pathologically and clinically., Methods: Using resected lung specimens, we first evaluated the distribution of MAC as well as the distribution of myofibroblasts in MAC lung infection according to several pathological findings classified as bronchiectasis, centrilobular nodules, cavity, nodules, bronchiolitis, or consolidation. Resected lung specimens (9 cases) were evaluated by special staining: Ziehl-Neelsen's method and immunohistochemically for CD68 (stain for monocytes and macrophages) and alpha-smooth muscle actin (stain for myofibroblasts). Chest CT findings were also examined in these 9 patients. In addition, the serial chest CT scans were reviewed in another 3 patients to evaluate the process of cavity formation, radiologically., Results: Although extensive granuloma formations were observed in every pathological classification, MAC was demonstrated only in the necrotic tissue of the inner surface of the cavitary wall, which was connected to the airway. Myofibroblasts which expressed alpha-smooth muscle actin were intensely demonstrated in the cavitary wall compared with other pathological classifications. In the cavitary wall, the layer of epithelioid cells and multinucleated giant cells surrounded necrosis, and the layer of myofibroblasts surrounded the layer of epithelioid cells. Chest CT findings demonstrated that the cavitary walls were relatively thick. The evaluation of serial chest CT scans demonstrated that cavities were formed from previously existing nodules., Conclusions: Detection of mycobacteria in the cavitary wall, massive infiltration of myofibroblasts compared with other pathological classifications, and connection to the drainage bronchus, were believed to be important in the process of cavity formation in MAC pulmonary infection.

We previously reported that T-cadherin (CDH13, H-cadherin), a unique cadherin molecule, was expressed on the basal cell layer in normal murine and human epidermis. In the present study, T-cadherin expression in archival human skin specimens comprising a spectrum of human squamous cell neoplasia was investigated. T-cadherin expression was observed in both normal epidermal basal cells and adnexal epithelial cells of formalin-fixed and paraffin-embedded tissue sections. Western immunoblotting also revealed that mature T-cadherin protein was expressed in cultured human skin tissue equivalent. Atypical keratinocytes in 27 of 53 specimens of actinic keratosis and 23 of 30 specimens of Bowen's disease expressed T-cadherin. In contrast, T-cadherin was focally expressed in 6 of 56 invasive cutaneous squamous cell carcinomas. To explore the molecular mechanism of down-regulation of T-cadherin expression in invasive squamous cell carcinoma, loss of heterozygosity, genetic alternations, and methylation status in the 5' region of the T-cadherin gene were investigated. Loss of heterozygosity at intron 1 of the T-cadherin gene was observed in 8 of 28 informative cases of invasive squamous cell carcinoma. Although no structural genomic alternations were found by sequence analysis, aberrant promoter methylation of the T-cadherin gene was found in 12 of 28 invasive squamous cell carcinomas. T-cadherin expression was restored in cultured A431 cells, in which aberrant methylation was found by treatment with the demethylating agent 5'-aza-2-deoxycytidine. These findings suggest that a combination of deletion and aberrant methylation of the T-cadherin gene may play a role in loss of gene expression in a considerable number of invasive cutaneous squamous cell carcinomas.

A case of multilobar bronchioloalveolar carcinoma (BAC) is reported. To investigate the clonality of BAC, immunohistochemical staining as well as genetic analysis were performed. To investigate point mutations of the p53 gene, we used the polymerase chain reaction and fluorescence-based single strand conformation polymorphism analysis method. The BAC tissues of the right upper lobe, right lower lobe, and the other lobes were considered to be multiclonal. This case suggests that multilobar BAC might occur with multiclonality.

Purpose: It is known that a common p53 polymorphism, encodingeither proline (Pro) or arginine (Arg) at residue 72, produces marked change in the structure of p53. Furthermore, the Arg72-containing allele is preferentially mutated and retained in various human tumors, suggesting that polymorphic residue within p53 modifies mutant behavior. We studied to determine whether Arg72 could be a risk factor for p53 mutations in human transitional cell carcinomas (TCCs). In addition, the relationship between the status of p53 codon 72 polymorphism and clinicopathological factors of this tumor were also analyzed., Experimental Design: We analyzed the correlation between the p53 mutations and genotypes of its codon 72 using genomic DNAs from the TCCs by direct DNA sequencing. Loss of heterozygosity was determined using a p53 microsatellite marker (TP53) amplified by PCR., Results: There was a bias to mutate and express the Arg allele in the p53 -mutated TCCs arising in individuals with heterozygosity (Pro/Arg). The Arg72-containing allele was preferentially retained in these tumors. The prevalence of cases with p53 mutations within Arg72-containing allele was higher for advanced-stage TCCs (chi(2) = 5.320, P = 0.021) than for TCCs with those arising in Pro72-containing allele., Conclusions: Our in vivo findings suggested that p53 mutation alleles containing Arg72 are preferentially selected during tumorigenesis and affect mutant behavior in TCCs, and revealed that TCCs with p53 mutation arising in Arg72-containing allele became progressively more abundant with increase in tumor stage.

A 64-year-old man was admitted to our hospital complaining of Hugh-Jones II dyspnea. Chest CT showed multiple diffuse patchy shadows in both lung fields. A diagnosis of pulmonary carcinomatous lymphangiosis was made on the basis of the presence of adenocarcinoma cells within the lymphatic vessels in transbronchial lung biopsy (TBLB) specimens. The primary site was a tumor in the stomach. It is very rare for pulmonary carcinomatous lymphangiosis to show multiple patchy shadows in CT. Tumor cells were positive for CA 19-9. There were high titers of carbohydrate antigens, SPAN-1, CA 19-9, SLX, CA 125 and CA 724 both in the bronchial alveolar fluid (BALF) and in the serum. SPAN-1, CA 19-9 and SLX titers were higher in the BALF than in the serum. In this case, liver metastasis had also occurred with carcinomatous lymphangiosis. This case is very interesting in that type I and II carbohydrate antigens were correlated with blood-borne metastasis.

Post-transcriptional modification of p53 by phosphorylation has been proposed to be an important mechanism of p53 stabilization and functional regulation. Phosphorylation of p53 Ser392, in particular, activates specific DNA binding functions by stabilizing p53 tetramer formation. This study evaluated the relationship between p53 Ser392 phosphorylation and various types of p53 missense mutation detected in urothelial transitional cell carcinomas (TCCs), with stratification of the mutations according to the functional domains elucidated by the crystal structure of the p53 protein. Of 41 TCCs with missense mutations, 26 (63.4%) exhibited immunopositivity with Ser392 phospho-specific p53 antibody. In comparison to structural mutations, the missense mutations at exon 7 (p=0.0307) or located in regions that affect direct DNA binding ability (p = 0.0273) were significantly associated with Ser392 immunopositivity. No statistically significant relationship was found between Ser392 immunoreactivity and other different types of p53 mutation. The prevalence of cases exhibiting Ser392-positive immunostaining was higher for high-grade (p <0.0001) and advanced-stage TCCs (p =0.0119) than for TCCs with wild-type p53. No significant relationship was found between Ser392 immunoreactivity and apoptotic index in urothelial TCCs. These in vivo findings indicate that Ser392 phosphorylation frequently occurs in mutant form p53 in TCCs. Because mutant form p53 can act dominant-negatively by heterooligomerization with wild-type p53, these findings also suggest that Ser392 phosphorylation might activate tetramer formation to promote the dominant-negative effects of mutant form p53, and thereby contribute to proliferation of aggressive TCCs.

Pathologic features of Mycoplasma pneumoniae infection (M. pneumonia) are generally non-specific, and the literature regarding the pathologic features of M. pneumonia with intraalveolar exudates is limited. Clinical and histopathological studies were performed in 3 patients with M. pneumonia which did not respond to erythromycin and minocycline, but all rapidly recovered after corticosteroid therapy. In pathologic findings, we observed intraalveolar exudates and focal organization in M. pneumonia, and its intraalveolar lesions were compared between M. pneumonia and bronchiolitis obliterans organizing pneumonia containing fibrin (BOOP). Immunohistochemical studies were performed using the streptavidin biotin peroxidase complex method with anti-alpha-smooth muscle actin antibody and anti-pancytokeratin AE1/AE3 antibody. In pathologic findings, more fibrin deposits in intaalveolar lesions were observed in M. pneumonia than in BOOP. In intaalveolar lesions of M. pneumonia, a larger amount of nuclear debris, more neutrophils, and more erythrocytes were noted. Myofibroblasts were observed in the organization of BOOP, while in the intaalveolar lesions of M. pneumonia, myofibroblasts were not observed. These results suggest that M. pneumonia with intraalveolar exudates responds well to corticosteroid and its intraalveolar lesions apparently differed from those in BOOP.

Leu-7 positive lymphocytes, including natural killer cells, play an important role in the immune system's surveillance function to prevent the development of cancer. The incidence of lung cancer is significantly high in patients with end-stage pulmonary fibrosis. We hypothesized that the number of Leu-7 positive cells may be decreased in areas of severe pulmonary fibrosis. To demonstrate this, Leu-7 positive cells were immunohistochemically stained in 41 lung specimens obtained from patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with collagen vascular disorders. The number of Leu-7 positive cells was evaluated according to the pathological findings. In pathologically normal lung, Leu-7 positive cells were mostly found within the capillaries of the septa and rarely in the alveolar space or the stroma. The number of Leu-7 positive cells was 0.69 +/- 0.15 in areas of advanced fibrosis (n = 41), 2.39 +/- 0.60 in areas that had newly developeing fibrosis (n = 41), 1.14 +/- 0.57 in bronchiolitis obliterans organizing pneumonia (n = 9), and 1.35 +/- 0.87 in diffuse alveolar damage (DAD) (n = 11). The number of Leu-7 positive cells in areas of newly developing fibrosis (2.39 +/- 0.60) was significantly higher than that in areas of established fibrosis (0.69 +/- 0.15, P < 0.05). Our present study demonstrates a significant decrease in the number of Leu-7 positive cells in areas of advanced fibrosis. This evidence may partly explain the high incidence of lung cancer associated with pulmonary fibrosis.

The present study was designed to evaluate the distribution of epithelioid cells, myofibroblasts, and TGF-beta1 in the formation of granuloma caused by Mycobacterium avium intracellulare complex (MAC) lung infection. A retrospective study was performed for 9 cases of positive MAC culture in which lung resections were performed between January 1989 and August 1999. Resected lung specimens were evaluated histologically and immunohistochemically for CD68 (stain for monocytes and macrophages, and epithelioid cells) and alpha-smooth muscle actin as well as vimentin (stain for myofibroblasts), and TGF-beta1 was performed. When granuloma was initially formed, no myofibroblasts were found, but as caseous necrosis appeared, the thin epithelioid cell layer was detected and the outer myofibroblast layer gradually became thick. In the cavitary wall, the layer of epithelioid cells and multinucleated giant cells surrounded necrosis, and was associated with the outer layer of myofibroblasts. In addition, the anti-TGF-beta1 antibody stained the cytoplasm of epithelioid cells and multinucleated giant cells, preceding the advent of myofibroblasts. In summary, our present study evaluated distributions of epithelioid cells, myofibroblasts, and TGF-beta along with the morphogenesis of granuloma, and clearly demonstrated the immunohistochemical difference between granuloma with caseous necrosis and granulomas without caseous necrosis.

It has been reported that the cytokeratin 19 (CK19) fragment, CYFRA 21-1, is increased in sera of some hepatocellular carcinoma patients. We hypothesized that CYFRA 21-1 might be released directly from hepatocellular carcinoma. To investigate this mechanism, we evaluated expression of CK19 in 8 human cell lines by immunoradiometric assay, Western blotting, immunohistochemistry, and reverse transcriptase-polymerase chain reaction in Chang liver cells, 2 cholangiocarcinoma cell lines, and 5 hepatocellular carcinoma cell lines. Three of 5 hepatocellular carcinoma cell lines released CYFRA 21-1, synthesized CK19 protein and expressed mRNA for CK19, as observed in 2 cholangiocarcinoma cell lines. In contrast, there was no expression of CK19 in Chang liver cells or 2 of 5 hepatocellular carcinoma cell lines. Analysis of genomic DNA for CK19 demonstrated that exon 1 was not amplified in the 3 cell lines not expressing CK19. However, there were no point mutations within exon 1 and the promoter region of CK19 in hepatocellular carcinoma cell lines. Our present study demonstrates that: i) the expression of CK19 was evident in some human hepatocellular carcinoma cell lines, and ii) the expression of mRNA for CK19 was related to the release of CYFRA 21-1. These results partially clarify the mechanism by which some hepatocellular carcinoma cell lines produce CK19 and others do not.

The first case of multifocal eccrine spiradenomas on the hand, forearm and scalp is described. This case is unusual in that the tumors located on the little finger included the nail matrix and occurred in a linear/zosteriform distribution, resulting in a nail deformity. The nodules on the forearm and scalp were in a random distribution. Histologically, each tumor was highly cellular and composed of two cell types: small darkly staining basaloid cells and larger, pale cells. Ultrastructural observations often showed an intracellular lumen with numerous microvilli in larger pale-staining cells., (Copyright 2002 S. Karger AG, Basel)