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Abstract Background We studied the expression of DMBT1 (deleted in malignant brain tumor 1), a putative tumor suppressor gene, in normal, proliferative, and malignant breast epithelium and its possible relation to cell cycle. Methods Sections from 17 benign lesions and 55 carcinomas were immunostained with anti DMBT1 antibody (DMBTh12) and sections from 36 samples, were double-stained also with anti MCM5, one of the 6 pre-replicative complex proteins with cell proliferation-licensing functions. DMBT1 gene expression at mRNA level was assessed by RT-PCR in frozen tissues samples from 39 patients. Results Normal glands and hyperplastic epithelium in benign lesions displayed a luminal polarized DMBTh12 immunoreactivity. Normal and hyperplastic epithelium adjacent to carcinomas showed a loss of polarization, with immunostaining present in basal and perinuclear cytoplasmic compartments. DMBT1 protein expression was down-regulated in the cancerous lesions compared to the normal and/or hyperplastic epithelium adjacent to carcinomas (3/55 positive carcinomas versus 33/42 positive normal/hyperplastic epithelia; p = 0.0001). In 72% of cases RT-PCR confirmed immunohistochemical results. Most of normal and hyperplastic mammary cells positive with DMBTh12 were also MCM5-positive. Conclusions The redistribution and up-regulation of DMBT1 in normal and hyperplastic tissues flanking malignant tumours and its down-regulation in carcinomas suggests a potential role in breast cancer. Moreover, the concomitant expression of DMTB1 and MCM5 suggests its possible association with the cell-cycle regulation.

Pulmonary arterial hypertension (PAH) includes various forms of pulmonary hypertension of different etiology but similar clinical presentation and functional derangement. Histopathological vascular changes in all forms of PAH are qualitatively similar but with quantitative differences in the distribution and prevalence of pathological changes in various portions of the pulmonary vascular bed. The documentation of these topographic variations in the response of the pulmonary vasculature to injury may be important to understand the pathogenesis of the various subsets of PAH. To standardize the precise histopathological documentation of the pulmonary vasculopathy in PAH we propose a histopathological classification that includes both the predominant segment of the pulmonary vasculature affected and the possible coexistence of pathological changes in other vascular segments.

Oxidative endothelial stress, leukocyte transmigration, and pulmonary thrombosis are important pathological factors in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Vascular immunotargeting of the H(2)O(2)-generating enzyme glucose oxidase (GOX) to the pulmonary endothelium causes an acute oxidative lung injury in mice.(1) In the present study we compared the pulmonary thrombosis and leukocyte transmigration caused by GOX targeting to the endothelial antigens platelet-endothelial cell adhesion molecule (PECAM) and thrombomodulin (TM). Both anti-PECAM and anti-TM delivered similar amounts of (125)I-GOX to the lungs and caused a dose-dependent, tissue-selective lung injury manifested within 2 to 4 hours by high lethality, vascular congestion, polymorphonuclear neutrophil (PMN) sequestration in the pulmonary vasculature, severe pulmonary edema, and tissue oxidation, yet at an equal dose, anti-TM/GOX inflicted more severe lung injury than anti-PECAM/GOX. Moreover, anti-TM/GOX-induced injury was accompanied by PMN transmigration in the alveolar space, whereas anti-PECAM/GOX-induced injury was accompanied by PMN degranulation within vascular lumen without PMN transmigration, likely because of PECAM blockage. Anti-TM/GOX caused markedly more severe pulmonary thrombosis than anti-PECAM/GOX, likely because of TM inhibition. These results indicate that blocking of specific endothelial antigens by GOX immunotargeting modulates important pathological features of the lung injury initiated by local generation of H(2)O(2) and that this approach provides specific and robust models of diverse variants of human ALI/ARDS in mice. In particular, anti-TM/GOX causes lung injury combining oxidative, prothrombotic, and inflammatory components characteristic of the complex pathological picture seen in human ALI/ARDS.

Clear cell mesothelioma is an extremely rare neoplasm of the pleura, which can easily be mistaken for a metastasis of clear cell carcinoma to the pleura. We report here the histochemical, immunohistochemical, and ultrastructural aspects of a new case of clear cell pleural mesothelioma in a 52-year-old man with no known asbestos exposure. He was admitted to the hospital for recurrent pleural effusion, which was negative for neoplastic cells at the cytologic examination. A partial decortication of the right pleura was performed. The morphologic, immunohistochemical, and ultrastructural features reported for this case are consistent with the diagnosis of clear cell mesothelioma. The differential diagnosis and immunohistochemical features in comparison with other clear cell neoplasms are discussed.

We studied the presence of surfactant protein A (Sp-A) immunoreactivity and messenger RNA in 62 normal and abnormal breast samples. Sections were immunostained with polyclonal anti-Sp-A antibody. The association between Sp-A immunoreactivity and histologic grade of 32 invasive ductal carcinomas was assessed by 3 pathologists who scored the intensity of Sp-A immunoreactivity times the percentage of tumor immunostained; individual scores were averaged, and the final scores were correlated with tumor grade, proliferative index, and expression of estrogen and progesterone receptors. Strong Sp-A immunoreactivity was present at the luminal surface of ductal epithelial cells in normal breast samples and in benign lesions; carcinomas displayed variable immunoreactivity, inversely proportional to the degree of differentiation. Sp-A messenger RNA was detected by reverse transcriptase-polymerase chain reaction in 3 of 3 normal breast samples and 9 of 9 carcinomas. The significance of Sp-A expression in breast epithelium requires further study; possibly it has a role in native host defense or epithelial differentiation.

Meningiomas are common, usually benign slow-growing neoplasms of the central nervous system thought to arise from meningocytes capping arachnoid villi. Primary ectopic meningiomas are exceedingly rare extracranial and extraspinal tumors of controversial origin; they are usually limited to the head and neck region or to the paravertebral soft tissues. Only one mediastinal ectopic meningioma and few pulmonary ectopic meningiomas have been described in the literature until now. Because of their rarity and their intriguing pathogenesis, we report here a second case of primary mediastinal meningioma and an additional case of primary pulmonary meningioma. Their possible origin and differential diagnosis are discussed.

Rat surfactant protein (SP)-C is a 3.7-kD hydrophobic lung-specific protein generated from proteolytic processing of a 21-kD propeptide (SP-C(21)). We have demonstrated that initial post-translational processing of SP-C(21) involves two cleavages of the COOH-terminus (Beers and colleagues, J. Biol. Chem. 1994;269:20,318--20,328). The goal of the current study was to define processing and function of the NH(2)-terminal flanking domain. Epitope-specific antisera directed against spatially distinct regions of the NH(2) terminus, NPROSP-C(2-9) (epitope = D(2)-L(9)) and NPROSP-C(11-23) (= E(11)-Q(23)) were produced. By Western blotting, both antisera identified SP-C(21) in microsomes. A 6-kD form (SP-C(6)), enriched in lamellar bodies (LBs), was detected only by NPROSP-C(11-23) and not extractable with NaCO(3) treatment. Immunogold staining of ultrathin lung sections with NPROSP-C(11-23) identified proSP-C in both multivesicular bodies (mvb) and LBs whereas NPROSP-C(2-9) labeled only mvb. (35)S-pulse chase analysis demonstrated synthesis of SP-C(21) and three intermediate forms (SP-C(16), SP-C(7), and SP-C(6)). Complete processing involved four separate cleavages with a precursor- product relationship between the low molecular weight forms SP-C(7) and SP-C(6). Fluorescence microscopy of A549 cells expressing fusion proteins of enhanced green fluorescent protein (EGFP) and proSP-C NH(2)-terminal deletion mutants showed targeting of EGFP/SP-C(1-194) and EGFP/SP-C(10-194) to early endosomal antigen-1-negative, CD-63-positive cytoplasmic vesicles whereas EGFP/SP-C(19-194), EGFP/SP-C(Delta 10-18), and EGFP/SP-C(24-194) were restricted to the endoplasmic reticulum (ER). We conclude that synthetic processing includes a previously unrecognized cleavage of the proximal NH(2) terminus (M(1)-L(9)), which occurs after removal of COOH-flanking domains (H(59)-I(194)) but before packaging in LBs, and that the region M(10)-T(18) is required for targeting of proSP-C to post-ER vesicular compartments in the biosynthetic pathway.

Aim of this work was to investigate the ability of the antibodies against Surfactant proteins (SP) and Thyroid transcription factor 1 (TTF-1) to distinguish primary neoplasms of the lung from metastatic carcinomas to the lung and pleural mesotheliomas. We evaluated the immunohistochemical expression of the antibodies anti SP-A, SP-B, pro SP-C, SP-D, and TTF-1 in a series of 56 primary lung carcinomas, 9 metastatic carcinomas to the lung, 5 pleural mesotheliomas and 8 non-pulmonary carcinomas. Among primary lung neoplasms, only adenocarcinomas immunostained for all SP (specificity = 1; total sensitivity = 0.52). TTF-1 had an excellent specificity (= 1), but a weak sensitivity (= 0.34) in recognizing primary lung carcinomas. TTF-1 was present in lung adenocarcinomas which were negative for SPs; however it failed to distinguish the subtypes. Pleural mesotheliomas, pulmonary metastases and non-pulmonary carcinomas were not immunoreactive for SP-A, SP-B, SP-D, and TTF-1. Pro SP-C was positive also in the adenocarcinomas of the large bowel and in their pulmonary and nodal metastases. These results demonstrate that the combined use of antibodies anti SP-A, SP-B and TTF-1 is the best association in distinguishing primary lung carcinomas from metastatic carcinomas to the lung and pleural mesotheliomas.

Vascular immunotargeting is a novel approach for site-selective drug delivery to endothelium. To validate the strategy, we conjugated glucose oxidase (GOX) via streptavidin with antibodies to the endothelial cell surface antigen platelet endothelial cell adhesion molecule (PECAM). Previous work documented that 1) anti-PECAM-streptavidin carrier accumulates in the lungs after intravenous injection in animals and 2) anti-PECAM-GOX binds to, enters, and kills endothelium via intracellular H(2)O(2) generation in cell culture. In the present work, we studied the targeting and effect of anti-PECAM-GOX in animals. Anti-PECAM-GOX, but not IgG-GOX, accumulated in the isolated rat lungs, produced H(2)O(2,) and caused endothelial injury manifested by a fourfold elevation of angiotensin-converting enzyme activity in the perfusate. In intact mice, anti-PECAM-GOX accumulated in the lungs (27 +/- 9 vs. 2.4 +/- 0.3% injected dose/g for IgG-GOX) and caused severe lung injury and 95% lethality within hours after intravenous injection. Endothelial disruption and blebbing, elevated lung wet-to-dry ratio, and interstitial and alveolar edema indicated that anti-PECAM-GOX damaged pulmonary endothelium. The vascular injury in the lungs was associated with positive immunostaining for iPF(2alpha)-III isoprostane, a marker for oxidative stress. In contrast, IgG-GOX caused a minor lung injury and little (5%) lethality. Anti-PECAM conjugated with inert proteins induced no death or lung injury. None of the conjugates caused major injury to other internal organs. These results indicate that an immunotargeting strategy can deliver an active enzyme to selected target cells in intact animals. Anti-PECAM-GOX provides a novel model of oxidative injury to the pulmonary endothelium in vivo.

Peripheral papillary adenomas of the lung are uncommon neoplasms (only ten cases have been described so far in the English literature) composed predominantly of type-II pneumocytes and generally considered benign. We describe here two additional cases of this lung tumor. In both cases histological examination revealed an encapsulated papillary neoplasm with invasion of the capsule and, in one case, invasion of the adjacent alveoli and visceral pleura too. The proliferative index (Ki67) was less than 2% and the epithelial cells were positive for cytokeratins, surfactant apoproteins (SP), and nuclear thyroid transcription factor-1 (TTF- 1). Ultrastructurally, the epithelial cells showed the characteristic surface microvilli and cytoplasmic lamellar inclusions of type-II cells. Review of the literature has revealed two other cases of peripheral papillary adenoma of type-II pneumocytes with infiltrative features. Thus, we propose replacing the term peripheral papillary adenoma with peripheral papillary tumor of undetermined malignant potential.

Anaplastic large cell lymphomas (ALCL) are a heterogeneous group of CD30+ large cell lymphomas; the most characteristic type have a T or null cell phenotype, often express epithelial membrane antigen (EMA) and cytolytic lymphocyte markers, and often possess a nonrandom t(2;5)(p23;q35) chromosomal translocation. We studied 22 (19 T, 1 null, 2 B cell) ALCL, including four primary cutaneous ALCL (PC-ALCL), for the expression of TIA-1, the cytotoxic T lymphocyte (CTL) or natural killer (NK) cell-associated antigens CD4, CD8, betaF1, TCRdelta1, CD56, and CD57, the ALCL-associated antigens p80 and EMA, and the Hodgkin's disease-associated marker CD15 to better define the relationship of these markers to histological subtype, primary site, and patient clinical characteristics. TIA-1 expression was seen in 12 of 20 (60%) T or null cell ALCLs with a cytoplasmic, granular distribution. Ultrastructural studies showed cytotoxic-type granules (dense core, multivesicular, and intermediate types) with TIA-1 localized to granules on immunogold labeling. TIA-1 staining strongly correlated with young patient age (< or = 32 years, P < .05) and EMA expression (P < .05). Excluding the four PC-ALCL cases, TIA-1 staining also correlated with p80 expression (P < .05) in all of the T cell cases. Three CD15+ cases were TIA-1-. TIA-1 expression in T or null cell ALCL was seen in all morphological subtypes (2 of 2 small cell variant, 3 of 4 monomorphic variant, and 7 of 14 pleomorphic variant) and primary tumor sites (6 of 14 nodal, 2 of 4 primary cutaneous, 2 of 2 bone, and 2 of 2 soft tissue). TIA-1+ granules were seen in all subsets: 5 of 6 CD4+, 1 of 2 CD8+, 4 of 8 CD56+, and 1 of 2 CD57+ ALCL. Of note, 4 of 10 T or null cell ALCL expressed gammadelta T-cell receptors (TCR), whereas only 1 of 10 T or null cell ALCL was alphabeta TCR+; TCR were not detected in five cases. TIA-1 was expressed by 3 of 4 gammadelta TCR+ ALCL and 1 of 1 alphabeta TCR+ ALCL. These data support a cytotoxic lymphocyte phenotype in most T or null cell ALCL and suggest that some T cell ALCL are derived from cytolytic CD4+ T cells, gammadelta T cells, or NK-like (CD56+ or CD57+) T cells.

Desmin myopathy is a rare idiopathic disorder characterized by abnormal aggregates of desmin-type intermediate filaments, which affects cardiac and skeletal muscle, and rarely the intestinal smooth muscle. We report a 42-year-old woman with atrial fibrillation and progressive restrictive cardiomyopathy. Left ventricular biopsy, cardiac explant, and subsequent autopsy study of skeletal muscle revealed cytoplasmic granulo-filamentous inclusions that were continuous with Z-lines and were immunoreactive for desmin filaments both at the light immunohistochemical and electron microscopic level. In addition, we report the presence of characteristic inclusions within the smooth muscle of intramural coronary blood vessels. This is the first description of desmin inclusions within vascular smooth muscle, and underscores the systemic nature of this rare myopathy.

We report a case of malignant mesothelioma with unusual clinical and histological findings. The patient presented with recurrent hydropneumothorax and minimal pleural thickening on chest computed tomography (CT). Histologically, the pleura was involved by the malignant mesothelioma, albeit to a limited degree. Unexpectedly, the lung parenchyma from two different lobes showed focal nests of mesothelioma cells filling the alveolar spaces and growing on the luminal surface of the alveolar septa, closely resembling the multicentric growth pattern of bronchioloalveolar adenocarcinoma. Immunohistochemical and ultrastructural studies confirmed that the pulmonary lesions were an extension of the malignant mesothelioma. This case illustrates clinically, the importance of a high index of suspicion for malignancy in older patients with unexplained recurrent hydropneumothorax; and histologically the potential of malignant mesothelioma to invade the lung at an early stage of growth.

Background: Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD) is a serious complication of lung transplantation. Besides immunosuppression the risk factors for PTLD development are largely unknown., Methods: The incidence of PTLD was ascertained in a lung transplant population consisting of 45 patients. Nine patients (20%) experienced PTLD. The clinical, histologic, and human leukocyte antigen (HLA) data were collected on all patients. The incidence of EBV infection in lymphoid tissue taken at the time of engraftment was studied by using EBV in situ hybridization., Results: All patients with PTLD had polymorphous lymphoproliferations, seven of which were polymorphous B-cell hyperplasias and two of which were polymorphous B-cell lymphomas. EBV was identified in all lesions. All patients with polymorphous B-cell hyperplasias had clinically unsuspected disease, five of which were identified at autopsy. The two polymorphous B-cell lymphoma lesions were monoclonal and regressed with immunosuppression reduction. EBV in situ hybridization on donor or recipient lymph nodes obtained at engraftment from the 45 transplant recipients showed no difference in the number of EBV positive cells in patients with and without PTLD. Cyclosporine and PTLD and azathioprine dosages and cyclosporine levels were similar between patients with and without PTLD. PTLD was seen in patients with high cumulative doses of antilymphocyte globulin. Analysis of HLA status showed a predominance of HLA A2 and DR7 in the donors of the patients with PTLD, whereas donor HLA B7 was more common in patients without PTLD>, Conclusions: Detailed studies are necessary to further elucidate the risk factors for PTLD development in the lung transplant population.

Background: Respiratory syncytial virus (RSV) pneumonia in immunocompromised patients, especially bone marrow transplant recipients, is associated with high mortality. Early diagnosis in these cases is important because antiviral therapy with ribavirin is effective in reducing mortality., Case: A 45-year-old male with multiple myeloma who underwent autologous peripheral stem cell transplantation subsequently developed bilateral pulmonary infiltrates. A bronchoalveolar lavage specimen demonstrated the cytologic changes associated with RSV pneumonia. Infection with RSV was confirmed by indirect immunofluorescence, enzyme immunoassay and, later, on histology and electron microscopy at autopsy., Conclusion: Recognition of the cytologic changes associated with RSV pneumonia in immunodeficient patients can be life saving since this would initiate confirmatory immunologic studies and therapy.

Fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) was used to detect sites of protein leakage in rat lungs perfused for 15-60 min with H2O2 (75, 150, and 300 microM). Leaky vessels were localized by confocal laser microscopy. Endothelial routes of protein leakage were identified by electron microscopy after photo-conversion of FITC-BSA to an osmiophilic diaminobenzidine product. Transport of FITC-BSA into the alveolar interstitium was assessed by immunogold labeling and anti-FITC antibodies. We detected leakage of FITC-BSA through transendothelial gaps in the pulmonary arterial endothelium after 30 min of perfusion with 300 microM H2O2 and after 60 min of perfusion with 150 microM H2O2. Junctional permeability and distribution of ZO-1 protein in the arterial endothelium were unchanged. Microvascular permeability to FITC-BSA was not increased in lungs perfused with H2O2. In lungs perfused with 300 microM H2O2, progressive extravasation of albumin was associated with significant increases in water content and perfusing pressure. We conclude that the pulmonary arterial endothelium is the primary target of circulating H2O2.

Adenovirus infection is a rare, but serious infection, during the neonatal period. The actual model of infection at birth is currently unknown, however, several mechanisms have been proposed. We describe a case of fatal neonatal adenovirus pneumonia in a 25-wk gestational age infant. Adenovirus was confirmed by electron microscopy and by in situ hybridization. The maternal cervical/endocervical smear taken prior to the delivery contained epithelial cells with changes suggestive of adenovirus, which was confirmed by in situ hybridization on the smear. These findings suggest that ascending viral infection is a factor in the pathogenesis of neonatal adenovirus infection. The identification and reporting of adenovirus may be important during pregnancy in order to avoid delay in delivery of the fetus once membranes have ruptured.

A 42-yr-old man who exsanguinated from an acute upper gastrointestinal bleed was found to have a primary aortoduodenal fistula on postmortem examination. The fistula arose in an aortic pseudoaneurysm associated with cystic medial necrosis. Although there was no suggestion of Marfan's syndrome on physical examination, there was cystic medial necrosis of not only the involved aorta, but also other systemic arteries. Primary aortoduodenal fistula is a rare cause of acute upper gastrointestinal bleeding and is usually associated with atherosclerotic disease of the aorta. This is the first report of a pseudoaneurysm associated with cystic medial necrosis presenting as an aortoduodenal fistula.

Eighteen stranded Atlantic bottlenose dolphins (Tursiops truncatus) examined postmortem were sampled for histologic study. All cases were examined for ferric ion and lipofuscin. Ages were determined from tooth growth layers. Electron microscopic (EM) examination and X-ray spectroscopy (EDAX) were performed. Chemical analysis for mercury was conducted on 12 of the animals by atomic absorption spectrophotometry. Nine animals were found to have excessive lipofuscin in both liver and kidney. Four of these nine animals also exhibited active liver disease (fat globules, central necrosis, lymphocytic infiltrates) whereas, of the animals without the excessive pigment, only one animal had an active liver lesion. EM and EDAX showed electron-dense amorphous material presumably within lysosomes to be Hg with no deposits on mitochondrial or nuclear membranes noted. Age relationship to portal pigment deposition was positive. Liver mercury concentrations ranged from 0.01 to 443 micrograms/g of wet weight with all animals having liver pigment yielding values of or above 61 micrograms/g, whereas all animals lacking pigment had values of or below 50 micrograms/g. The evidence suggests that the excessive pigment accumulation is related to toxic effects of Hg and presents as increased active liver disease.

Total parenteral nutrition is required by all patients in need of small bowel transplantation. Untoward side effects of total parenteral nutrition include atrophy and hypofunction of the small intestine. Glutamine, the preferred fuel for the enterocyte, is presumably present in insufficient amounts in diets given to patients with intestinal dysfunction. In a rat model of total parenteral nutrition and small bowel transplantation, this study investigated the following: (1) whether glutamine improves graft structure and function, (2) the optimal route of glutamine delivery (intravenous vs direct infusion into the graft), and (3) the effect of glutamine on ultrastructure of the graft enterocyte. Lewis rats underwent small bowel transplantation as a Thiry-Vella graft and received total parenteral nutrition for 14 days while assigned to one of four infusion groups: 2% intravenous glutamine; 2% intravenous isonitrogenous mixture, nonessential amino acids (control); 2% glutamine into the graft; or 2% nonessential amino acids into the graft (control). Graft mucosal villous height, villous surface area, crypt depth, weight, protein, deoxyribonucleic acid content, glucose absorption, and enterocyte ultrastructure were then evaluated. Infusion of glutamine directly into the graft significantly increased mucosal villous height (p = .045), surface area (p = .029), and glucose absorption (p = .004) when compared with controls. Intravenous glutamine infusion significantly increased mucosal villous height (p = .002), surface area (p = .001), weight (p = .005), and glucose absorption (p = .04) when compared with controls. Most enterotrophic and functional benefits of glutamine were not significantly different between intravenous infusions and direct administration into the graft.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent reports have suggested a possible association between HIV-1 infection and primary pulmonary hypertension (PPH), but most of the patients described to date have either had acquired immunodeficiency syndrome (AIDS) with concurrent lung infections or have administered Factor VIII intravenously for hemophilia. We report three human immunodeficiency virus type 1 (HIV-1)-positive homosexual white males with clinical and hemodynamic diagnoses of PPH. None of the patients had any opportunistic lung infections or other pulmonary pathology, nor were they hemophiliacs. They had no histories of intravenous drug use. Lung tissue from two of the patients revealed hypertensive arteriopathy consistent with PPH and no other pulmonary pathology. Attempts at localizing HIV-1 infection to the vascular endothelium with electron microscopy, immunohistochemistry, DNA in situ hybridization, and polymerase chain reaction techniques did not reveal direct pulmonary artery infection with the virus. These data and the finding of tubuloreticular structures on electron microscopy suggest that HIV-1 may play a role in the pathogenesis of these cases of PPH through mediator release associated with HIV-1 infection rather than by direct endothelial infection.

Pneumonopathies in association with graft-versus-host disease (GVHD) are known, but the evolution of biopsy-proven interstitial pneumonitis (IP) to pulmonary fibrosis as a major pulmonary manifestation in an individual patient with chronic GVHD has not been previously reported. We present a patient with chronic GVHD who developed IP and then pulmonary fibrosis. We suggest that IP with evolution to pulmonary fibrosis was a major pulmonary manifestation of chronic GVHD in this patient.

A cost-effective method for electron microscopic study of snap-frozen surgical specimens is described. The method is available to any surgical pathology laboratory equipped with a deep freezer and allows the performance of ultrastructural observations on archival material.

The authors report immunohistochemical and electron microscopic studies on three new cases of pseudomesotheliomatous carcinoma of the lung. Although the distinct clinical and histopathologic features of this peripheral lung cancer were described many years ago, its recognition as a distinct variety of lung carcinoma has not gained wide acceptance. Little is known of its incidence and only few cases have been reported until now. In the current study the authors demonstrate the epithelial nature of this tumor by its positive immunohistochemical reactions for epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), Leu-M1, B 72.3, and surfactant apoprotein. The ultrastructural features and staining of nuclear inclusions with surfactant apoprotein indicate differentiation into type II cells as found in other forms of peripheral lung adenocarcinoma. Despite these morphologic similarities, pseudomesotheliomatous carcinoma is characterized by extensive invasion of the pleura and rapidly fatal course. Because of this biologic behavior it deserves recognition as a distinct variant of peripheral lung carcinoma.

In six anesthetized and mechanically ventilated adult sheep, the bronchial artery was perfused with blood from an oxygenator-pump circuit. When the lungs were ventilated with 100% O2 and the bronchial O2 tension (PbrO2) was approximately 600 Torr, the mean of the pulmonary vascular resistances (PVR) measured at the beginning (3.32 +/- 0.29 units) and end (3.17 +/- 0.13 units) of the experiment was 3.24 +/- 0.20 units. When the PbrO2 was changed to 58 +/- 1 Torr, the PVR (2.99 +/- 0.14 units) did not change significantly. However, when the lungs were ventilated with air as PbrO2 was decreased to 91 +/- 4, 77 +/- 3, 56 +/- 2, and 42 +/- 1 Torr, the PVR increased to 3.67 +/- 0.18, 4.03 +/- 0.16, 4.79 +/- 0.19, and 4.71 +/- 0.35 units, respectively. However, when the PbrO2 was decreased further to 26 +/- 1 and 13 +/- 1 Torr, the PVR decreased to 3.77 +/- 0.28 and 3.91 +/- 0.30 units, respectively. In contrast, the bronchial vascular resistance decreased monotonically as PbrO2 decreased. The bronchial circulation supplies vasa vasorum to the walls of all but the smallest pulmonary arteries, and it is therefore suggested that the PO2 of the bronchial circulation is responsible for the bimodal response of the pulmonary vasculature, with stimulation of hypoxic pulmonary vasoconstriction at moderate hypoxemia and of hypoxic pulmonary vasodilation at profound hypoxemia. The physiological and pathophysiological significance of the influence of systemic PO2 on pulmonary vascular tone is discussed.

The pathology of drug-induced lung disease is approached on the basis of patterns of tissue reaction in this review. The entities described include various pathologic lesions, from diffuse alveolar damage to interstitial pneumonias and angiopathies. Because the histopathologic manifestations of drug injury are variable and nonspecific, pathogenetic mechanisms are emphasized. Drugs may cause injury by direct toxicity or by triggering immunologic responses, but often this neat distinction is blurred by the combined effects of preexisting lung injury and the concurrent administration of several drugs. Thus the identification of drug-induced lung disease requires thorough knowledge of the clinical history and rigorous analysis of histopathologic features.

We have investigated the effects of H2O2 (150 or 300 microM) on the ultrastructure and permeability of the pulmonary endothelium in rat lungs perfused for 60 min with buffered Hanks' bovine serum albumin medium. In one group of experiments, we examined the effect of H2O2 on the uptake and transport of cationized ferritin (CF) by endothelial cells in intra-acinar arteries, alveolar capillaries, and interlobular veins. The influence of the oxidant on endothelial adsorptive endocytic processes was assessed by measuring the density of ferritin particles in luminal vesicles, multivesicular bodies, and basal lamina. In a second group of experiments, we examined the effects of H2O2 on the fine structure and permeability to electron-dense macromolecules of arterial, microvascular, and venous endothelium. For this purpose, at the end of the 60-min perfusion with H2O2, CF was perfused to identify leaky vessels. We found that H2O2 caused a dose-dependent inhibition of transcytosis of CF in all vascular segments. At the lower dose of H2O2, inhibition of transcytotic activity was not associated with structural injury to the vascular endothelium or with elevation of wet-to-dry ratios. At the higher oxidant dose, inhibition of transcytosis was associated with leaky arterial endothelium and elevation of wet-to-dry ratios (6.44 +/- 0.12 vs. 5.64 +/- 0.16, P less than 0.02). The effects of H2)2 were prevented by adding catalase to the perfusate. The selective loss of structural integrity and leakiness of the arterial endothelium were diminished but not completely abolished by perfusing the oxidant retrograde from the venous side.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of unexplained (primary) pulmonary hypertension (PPH) rarely diagnosed during life and generally associated with a progressively deteriorating course. We describe three patients with PVOD; in two of them, diagnosis was established by open lung biopsy. All three patients underwent right heart catheterization and acute vasodilator testing, and each responded favorably to at least one test agent. One patient did not receive chronic vasodilator therapy and died seven months after his initial evaluation. The other two patients were treated with chronic vasodilator therapy; one initially improved, but then experienced progressive right heart failure and died 23 months after the start of therapy, the third patient is alive and clinically improved 72 months after beginning vasodilator therapy. Details of the vasodilator studies, and the rationale for treating this uncommon disorder, are provided.

The authors report two extremely unusual cases in which metastatic cancer was mimicked by mesothelial cell inclusions in mediastinal lymph nodes. The cells appeared only in the nodal sinuses and occurred predominantly as single individual cells and small clusters. The nuclei were bland, the N/C ratio was low, and the cell borders were well defined. So-called mesothelial windows were noted when cells formed groups; mitoses were not observed. Immunohistochemical analysis demonstrated the inclusions to be positive for cytokeratin (both AE1/3 and CAM5.2) but negative for epithelial membrane antigen, Leu-M1, and carcinoembryonic antigen. Nearly all cells were negative for B72.3; rare cells in one case contained unusual minute granular dot-like positivity in the region of the Golgi for this marker. The pattern of cytokeratin immunoreactivity was consistent with a mesothelial cell: namely, stronger immunoreactivity in a perinuclear location with some fading at the cell periphery. Ultrastructural analysis of both cases documented long microvilli processes consistent with a mesothelial origin. An extensive clinical workup in each case has failed to identify a primary carcinoma. It is interesting that both patients had a pleuritis with pleural effusion and both had mediastinal widening. In the first case, the exact cause of the benign pleural process was unknown but thought to be infectious. The second patient had follicular lymphoma in the same lymph node together with pleural involvement clinically and evidence of congestive heart failure. The patients are alive three years and ten months from diagnosis, respectively. Recognition of this new and previously unrecognized entity is important to prevent a diagnosis of carcinoma in such rare instances.

Lungs of 37 patients with pulmonary hypertension (PHT), 5 normal human lungs, and 30 normal rat lungs, were studied using immunohistochemical stainings for actin, alpha-smooth muscle (alpha-SM) actin and desmin. The type of PHT was determined on clinicopathologic grounds (in 17 cases by catheterism); 20 patients had precapillary and 17 postcapillary PHT. In normal lungs, myofibroblasts, ie, contractile interstitial cells (CIC), distributed in alveolar septa, were not stained by alpha-SM actin antibodies. Only around the venules, were cells labeled by this antibody present. Furthermore, there were bundles of alpha-SM actin-positive cells around the openings of air sacculi into the alveolar ducts. In precapillary PHT, the distribution and immunostaining properties of interstitial cells remained unchanged; alpha-SM actin-positive cells were observed in thickened arterial intima and in plexiform lesions. In postcapillary PHT secondary to heart failure, to mitral stenosis, or in veno-occlusive disease, many interstitial cells in the alveolar septa were decorated by alpha-SM actin antibodies but not with desmin. The authors propose that, in postcapillary PHT, mechanical stretch due to capillary congestion may be responsible for the generation of cells that express an actin isoform associated with smooth muscle.

Although commonly found at autopsy, leukemic infiltration of the lung is rarely recognized as a cause of respiratory symptoms or roentgenographic densities. Previously reported cases of patients who had symptomatic or roentgenographic acute leukemic lung diseases invariably presented with diffuse pulmonary infiltrates. We describe three patients with leukemic involvement of the lung who presented with cough, fever, and localized roentgenographic infiltrates suggestive of bacterial pneumonia. In each case, the diagnosis was made by transbronchial biopsy specimen and confirmed by complete response to chemotherapy. In common with the other reported cases, all of our patients had peripheral blast counts above 40 percent (greater than 6,000 blasts per ml3) at the time the pulmonary diagnosis was made. Leukemic invasion of the lung should be considered in patients with acute leukemia who develop lung infiltrates--whether diffuse or focal--in association with a high peripheral blast count.

Two plasma proteins, vitamin D-binding protein (actin monomer sequestrant) and gelsolin (actin polymer severing), have been found in association with actin in plasma from ill humans and during experimental injury. In vitro, these are the only plasma proteins that display a high affinity for actin. We infused increasing amounts of globular actin intravenously to rats to evaluate its disposition in plasma and tissues. Intravascular filament formation, microthrombi, and endothelial injury were observed, especially in the pulmonary circulation. These pathological changes were not observed when the globular actin in the infusate had been preincubated with the vitamin D-binding protein in vitro. Complexes of actin with both proteins were found in the plasma, suggesting a saturable, plasma actin-binding system in vivo. Our findings suggest that in vivo saturation of these proteins' actin-binding capacities may serve as a paradigm for pulmonary vascular disorders seen during widespread tissue trauma and cell lysis.

This chapter provides a brief description of the pathology of the most common primary lung carcinomas. While the basic morphologic concepts have remained nearly constant for many years, much has been learned from application of electron microscopy and immunohistochemistry. Application of DNA probes is just beginning, but it promises to further expand our understanding of the biology of these tumors. Clinical behavior and staging are discussed elsewhere in this issue. Since both stage and histologic type of a given lung tumor are important factors in determining management, with the increasing utilization of less invasive procedures for tissue sampling, it is essential for the pathologist to rely on new technological advances to make accurate diagnoses.

The fine structure of the secondary lamellae of gills was examined in two cold-water marine teleosts, the winter flounder, Pseudopleuronectes americanus, and the antarctic cod, Trematomus borchgrevinik. In both species the overall lamellar fine structure is similar to that of other marine teleosts. The major variations in cellular organization involve the distribution of both the "chloride cells" and the mucous cells on the secondary lamellae of P. americanus. At winter water temperatures of +2.5 degrees C, significantly more chloride and mucous cells are present than in summer with water temperatures of +15.2 degrees C. Both cell types are routinely present throughout the length of a secondary lamella as far as the lamellar tip. The chloride cells on the secondary lamellae are always situated in the inner layer of epithelium deep to the outer pavement cells. T. borchgrevinki shows no apparent difference in the distribution of mucous cells either at its normal water temperature of -1.9 degrees C or at a temperature of +4 degrees C, the upper limit of its thermal tolerance to which some specimens were adapted in the aquarium. Chloride cells were never observed on the secondary lamellae of T. borchgrevinki. This suggests that low environmental water temperatures may be related to the distribution of mucous cells and chloride cells on the secondary lamella of the teleost gill.

In order to characterize the alveolar response to Pneumocystis carinii pneumonia, light and electron miscropy were used to trace the development of experimental infections with P carinii in rats treated with cortisone acetate and a low-protein diet. The first changes were found by the eighth day of treatment and consisted of the selective attachment of Pneumocystis organisms, mostly trophozoites, to alveolar Type 1 pneumocytes; the host cells were undamaged, and no inflammatory response was seen. After approximately one month of treatment, the seemingly innocuous host-parasite interaction was succeeded by focal necrosis of the Type 1 pneumocytes adjacent to organisms; hyperplasia of nearby Type 2 pneumocytes also occurred, to replace the dead Type 1 pneumocytes. Even at this stage, inflammatory reaction was conspicuously absent except for occasional alveolar macrophages in the diseased alveoli; in addition, all cells of the alveolar-capillary membrane other than Type 1 pneumocytes appeared entirely normal. Not only does the present study clarify the nature of alveolar injury caused by Pneumocystis carinii, but it also provides an experimental animal model in which selective injury of the alveolar lining cells occurs.

Histamine causes interstitial pulmonary edema, but whether this is the result of an increased permeability of the pulmonary circulation or only of the bronchial circulation remains to be determined. In order to selectively study the effect of histamine on the pulmonary circulation, we used an isolated perfused rabbit lung preparation because in this species, the bronchial circulation is poorly developed. Edema formation was assessed by continuously monitoring the weight of the lung perfused at constant pressure. These studies were supplemented by electron microscopic observations using hemoglobin as an ultrastructural tracer for microvascular permeability. We found that histamine (8.0 microgram base/100 ml of perfusate) did not cause lung weight to increase. Ultrastructural studies showed that histamine, at this dosage, did not cause a greater leakage of hemoglobin that occurred in the control lungs. Thus, we have concluded that histamine does not increase the permeability of the pulmonary microcirculation in the isolated perfused rabbit lung.

Rats exposed to 30 ppm NO2 continuously for 3 to 6 wk developed mild centriacinar air-space enlargement and mild interstitial fibrosis. The emphysematous changes did not become more severe after 6 wk with continued NO2 exposure for as long as 14 additional weeks. Elastase inhibitory capacity (EIC) and the total protein concentration increased acutely in lung lavage fluid, consistent with the histologic evidence of pulmonary edema, then subsided but remained above control levels for the entire exposure period. The ratio of EIC to total protein remained unchanged relative to that in control animals. Neutrophils accumulated in the lung and were recoverable by lavage with the same relative concentration profile as observed for total protein. The average elastase activity per neutrophil in cells recovered from the air space by lung lavage was 60% less than in cells recovered from peripheral blood. This was true for control or NO2-exposed rats. Thus, emphysematous changes in the NO2-exposed rat were accompanied by a marked neutrophil recruitment concomitant with an increased neutrophil elastase burden in the lung, which may have directly contributed to lesion development.

In anticipation of the temporary relocation of Surgical Pathology some distance from the operating rooms, a "pneumatic" tube system was installed to transport fresh tissue from surgery to pathology at the Hospital of the University of Pennsylvania. The point-to-point 4-inch internal diameter system is actually of the blower or "pea-shooter" type. Side-opening carriers were preferred, and electronic sensors were installed for monitoring and safety. At the pathology end of the system, a complete panel of electrical controls exist that are capable of initiating the blower at either end, enabling full control. For possible future retrieval of stuck carriers, several points of mechanical entry were desired and constructed. The transit time over 886 feet varies with the weight of the specimen but averages 25-35 seconds. Thus far, after 32 months and 12,652 transits, no specimens have been lost or damaged. During the first few months, two specimens became stuck for reasons relating to human error but were easily retrieved. This system, in conjunction with operating room telephone intercoms, has become fully accepted and trusted by surgeons and pathologists.

Bronchioloalveolar carcinoma may present with a variety of radiologic and clinical patterns. Two types of this primary carcinoma of the lung have been recognized: a solitary lesion and a diffuse form. Charts and radiographs of 61 cases of bronchioloalveolar carcinoma were reviewed as well as the pertinent literature. Our experience indicates that the localized form seldom, if ever, becomes diffuse and has a good prognosis following appropriate surgery (lobectomy or pneumonectomy). If the lesion is diffuse, death almost invariably results within 3 years. Based on available clinical information, we suggest that at least two primary tumors of the lung have the histologic pattern of bronchioloalveolar carcinoma: one of these tumors is diffuse and the other is solitary.