Enhanced lipid peroxidation in lung lavage of rats after inhalation of asbestos.

Exposure of phagocytic cells to asbestos in vitro results in an augmented production of reactive oxygen metabolites and increased peroxidation of lipids. The aim of this investigation was to assess the extent of lipid peroxidation both in cells and fluid obtained from bronchoalveolar lavage (BAL), and in lungs of rats exposed to crocidolite asbestos or titanium dioxide (TiO2), a nonfibrous particulate control. In comparison to sham and TiO2-exposed rats, the BAL fluid and cells of crocidolite-exposed animals contained significantly elevated levels of malondialdehyde (MDA), a breakdown product of lipid peroxidation detected using high-pressure liquid chromatography (HPLC). In contrast, no significant differences in MDA were detected in lavaged lung tissue from these animals. Inhalation of crocidolite caused an early inflammatory response characterized by elevated numbers of polymorphonuclear leukocytes and lymphocytes, as well as enhanced total protein in BAL. Pulmonary fibrosis and increased lung hydroxyproline also were observed after 20 days of exposure. Exposure to TiO2 did not cause inflammation, pulmonary fibrosis, or elevated amounts of hydroxyproline in the lung. Our results show that exposure to the fibrogenic and inflammatory mineral, crocidolite, results in an enhanced lipid peroxidation in BAL cells and fluid not observed after inhalation of the particulate TiO2. These novel observations suggest that MDA in BAL may be useful as a biomarker of exposure to inhaled asbestos or other oxidants.

Micronodular pneumocyte hyperplasia.

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by mental retardation, seizures, and central nervous system and visceral hamartomas. Pulmonary involvement manifesting as lymphangioleiomyomatosis (LAM) occurs in 1% of patients (all women) with TSC. Micronodular pneumocyte hyperplasia also has been described as a rare pulmonary manifestation of TSC. We report 14 patients with micronodular pneumocyte hyperplasia (MNPH). The patients ranged in age from 23 to 57 years (mean 37.5). There were 12 women and 2 men. Nine of the patients (one man and eight women) had documented clinical manifestations of TSC: seven with LAM, two without LAM (including one man). Of the five patients who did not have TSC, three had LAM and two did not (including one man). Histologically, all 14 cases demonstrated multiple well-demarcated nodules usually measuring up to 8 mm in size, but most were 1-3 mm. The nodules were produced by a proliferation of enlarged cytologically benign type II pneumocytes, with an associated increase in alveolar macrophages and interstitial reticulin. Immunoperoxidase studies showed the type II pneumocytes within lesions to be reactive with antibodies to cytokeratin (four of four), epithelial membrane antigen (EMA) (five of five), and surfactant apoprotein B (8 of 10). HMB-45 was negative in the MNPH lesions in all nine cases studied. Follow-up was available in 9 of 10 living patients and ranged from 1 to 14 years (mean 6 years). Nine patients are alive; six are clinically stable and three have repeated pneumothoraces related to LAM. Four patients have died. None of the deaths were attributable to MNPH. MNPH appears to be a hamartomatous proliferation occurring most frequently in patients with tuberous sclerosis, is separable from and not a manifestation of LAM, has been observed to occur in men, and, like other hamartomas of tuberous sclerosis, does not appear to possess malignant potential.

Diagnostic accuracy of a rural live video telepathology system.

Accuracy of diagnoses rendered using a live video telepathology network was assessed for permanent sections of surgical pathology specimens. To determine accuracy, telepathology diagnoses were compared with those obtained by directly viewing the glass slide using a standard microscope. A total of 294 cases were read via both telepathology and glass slide by attending pathologists at a tertiary care medical center. Overall accuracy was defined as exact concordance between diagnoses. Clinically insignificant differences in diagnoses were excluded to determine clinically significant accuracy. For the 285 cases with complete data, the overall accuracy for telepathology was 0.912 (95% confidence interval [CI], 0.872-0.941), whereas the overall accuracy for glass slide readings was 0.968 (95% CI, 0.939-0.985). This difference is statistically significant (p = 0.009). When focusing on clinically significant discrepancies, where the difference in diagnosis might affect therapeutic decisions, the video accuracy was only slightly less than the glass slide accuracy (0.965 [95% CI, 0.934-0.982] vs. 0.982 [95% CI, 0.957-0.994], respectively), but this difference is not statistically significant (p = 0.302). Most of the cases with clinically significant differences involved lesions with inherently high interobserver variation. Certainty of diagnosis did not differ between video and glass slide readings (p = 0.911), but there was an association between certainty of diagnosis and diagnostic accuracy for video (p = 0.003 for clinically significant accuracies). Based on these findings, we recommend when using this telepathology system that only preliminary diagnoses should be given in the following situations: for diagnostic areas with known high interobserver variability; when the consultant has any degree of uncertainty about the presence or absence of the lesion in question; and when there is insufficient experience using telepathology as a diagnostic medium.

Lectin binding patterns to terminal sugars of rat lung alveolar epithelial cells.

We used post-embedding cytochemical techniques to investigate the lectin binding profiles of rat lung alveolar epithelial cells. Sections from rat lung embedded in the hydrophilic resin Lowicryl K4M were incubated either directly with a lectin-gold complex or with an unlabeled lectin followed by a specific glycoprotein-gold complex. The binding patterns of the five lectins used could be divided into three categories according to their reactivity with alveolar epithelial cells: (a) the Limax flavus lectin and Ricinus communis I lectin bound to both type I and type II cell plasma membranes; (b) the Helix pomatia lectin and Sambucus nigra L. lectin bound to type II but not type I cells; and (c) the Erythrina cristagalli lectin reacted with type I cells but was unreactive with type II cells. The specificity of staining was assessed by control experiments, including pre-absorption of the lectins with various oligosaccharides and enzymatic pre-treatment of sections with highly purified glycosidases to remove specific sugar residues. The results demonstrate that these lectins can be used to distinguish between type I and type II cells and would therefore be useful probes for investigating cell dynamics during lung development and remodeling.

Hepatic parenchymal lymphoid aggregates in Hodgkin's disease.

One hundred twenty-three liver biopsies performed at staging laparotomy for Hodgkin's disease were reviewed. Discrete parenchymal lymphoid infiltrates with variable cytologic atypia were identified in 12 patients. None of these patients had liver involvement by Hodgkin's disease. All 12 patients were alive with no clinical evidence of liver disease at last follow-up examination; however, two had extrahepatic relapses of Hodgkin's disease. Parenchymal lymphoid aggregates, a nonspecific finding in the livers of patients with Hodgkin's disease, may show some degree of cytologic atypia, but they do not represent lymphoma. Such aggregates may be relatively common and they may be overinterpreted as neoplastic, particularly in patients with non-Hodgkin's lymphoma.

Contractile cells of the kidney in primary glomerular disorders: an immunohistochemical study using an anti-alpha-smooth muscle actin monoclonal antibody.

Mesangial cells of the renal glomerulus are thought to have contractile properties, resembling those of smooth muscle cells. Since actin synthesis in mesangial cells is increased in selected animal models of glomerulonephritis, we evaluated the expression of alpha-smooth muscle actin (ASMA), the principal actin isoform found in smooth muscle cells, in biopsy specimens from patients with primary glomerular disorders and in control tissues. Normal glomeruli and glomeruli in acute tubulointerstitial disorders showed few or no ASMA-positive cells in the glomeruli. In contrast, ASMA expression in mesangial cells was increased in minimal change disease, focal segmental glomerulosclerosis, mesangial proliferative glomerulonephritis, membranous glomerulonephritis, and immunoglobulin A nephropathy. In membranoproliferative glomerulonephritis and cryoglobulinemic glomerulonephritis both mesangial and capillary loop ASMA-positive cells were observed with a segmental distribution. In addition, ASMA-positive interstitial cells were seen in many biopsy specimens and often were increased in number in biopsy specimens showing early interstitial fibrosis and tubular atrophy. We conclude that ASMA synthesis in mesangial cells is upregulated in a variety of glomerular disorders, frequently associated with increased cell proliferation and mesangial matrix production. This phenotypic change may be an indicator of mesangial cell activation after injury and may have important pathophysiologic consequences.

The bone marrow in systemic podophyllin toxicity.

The effects of systemic Podophyllin toxicity on the bone marrow are a manifestation of this agent's potent antimitotic activity. Our patient experienced a transient aregenerative anemia with leukopenia and thrombocytopenia. The bone marrow was hypocellular with cytoplasmic vacuolation of myeloid precursors and increased numbers of mitotic figures. Megakaryocytes were normal in number and morphology. Hematologic resolution followed discontinuance of topical therapy.

Second opinions in surgical pathology.

When to obtain opinions in anatomic pathology is a complex issue. The authors discuss the cognitive process of morphologic interpretation, the influence of expertise on the need for a second opinion, the role of ego, and the impact of economic factors on the patterns of consultation.

Postpartum hemophilia.

An acquired circulating inhibitor to Factor VIII:C was found in a 27-year-old postpartum woman who presented with ecchymoses and hematomas. Postpartum Factor VIII:C inhibitors can clinically manifest with signs and symptoms not unlike those in a classic hemophiliac. The natural history of this inhibitor is typically one of spontaneous disappearance with the return of the patient's previous hemostatic capacity. The authors describe a patient with the postpartum Factor VIII:C inhibitor, and discuss this unusual disease entity along with the therapeutic considerations.

Diffuse pulmonary disease caused by nontuberculous mycobacteria in immunocompetent people (hot tub lung).

The clinicopathologic spectrum of infections due to nontuberculous mycobacteria (NTM) includes cavitary disease, opportunistic infection, and nodular disease associated with bronchiectasis. We report a less well-described manifestation of NTM infection: 10 immunocompetent patients without preexisting bronchiectasis had radiographic evidence of diffuse infiltrative lung disease. The most common symptoms were dyspnea, cough, hypoxia, and fever. All 10 patients had used a hot tub. Histologic examination revealed exuberant nonnecrotizing, frequently bronchiolocentric, granulomatous inflammation in all cases. In 1 case, necrotizing granulomas were also noted. The inflammation often was associated with patchy chronic interstitial pneumonia and organization. Cultures revealed NTM in all cases (Mycobacterium avium complex in all but 1 case), but staining for acid-fast bacilli was positive in only 1 case. Four patients received corticosteroids alone for presumed hypersensitivity pneumonia, 4 were treated with antimycobacterial therapy, and 2 received both. All patients demonstrated significant improvement at the time of follow-up. These findings suggest that disease due to NTM may manifest as diffuse infiltrates in immunocompetent adults and that hot tub use may be an important risk factor for this disease pattern.

Osteocalcin and osteonectin immunoreactivity in the diagnosis of osteosarcoma.

Osteosarcomas (OSAs) can be difficult to distinguish histologically from tumors with significantly different biologic potentials and treatment protocols. The correct diagnosis of OSA relies on identification of malignant osteoblasts that are capable of producing neoplastic bone. To determine the use of immunohistochemistry for the diagnosis of OSA, 106 tumors from the Massachusetts General Hospital and the University of Vermont were immunostained with monoclonal antiosteocalcin (OC) and antiosteonectin (ON) antibodies. They included 42 OSAs, 25 non-bone-forming sarcomas, 24 other malignant tumors including lymphomas, carcinomas, and melanomas, and 15 benign bone tumors. Cytoplasmic staining with OC showed 70% sensitivity and 100% specificity, while staining with ON showed 90% sensitivity and 54% specificity for bone-forming tumors, consistently staining cell types other than osteoblasts. Of the OSAs, 83% demonstrated matrix staining with one or both antibodies, whereas dense collagen was negative for both antibodies in all tumors. We conclude that tumor cell cytoplasmic staining with monoclonal OC may be helpful in distinguishing OSAs from other malignancies, and staining of extracellular matrix for OC and ON antibodies concurrently may help distinguish bone matrix from dense collagen.

Recommendations for the reporting of resected neoplasms of the kidney. Association of Directors of Anatomical and Surgical Pathology.

The Association of Directors of Anatomic and Surgical Pathology has developed recommendations for the surgical pathology reporting of common malignant tumors. The recommendations for renal cell neoplasms are reported here.

Silicosis in mice: effects of dose, time, and genetic strain.

Experimental silicosis allows study of the mechanisms of lung injury, inflammation, and fibrosis. Inbred mice are an attractive species in which to study these mechanisms because of recent progress in murine immunology, molecular biology, and genetics. We exposed mice to an aerosol of silica and examined the effects of exposure dose, the evolution of disease features over time, and the variation in responses among four inbred strains. In C3H/HeN mice incremental cumulative exposure doses of cristobalite silica caused increased initial lung dust burden 12 to 16 weeks post-exposure, progressively intense pathological responses, and increased total lung collagen (hydroxyproline). The histopathological changes and total lung collagen increased progressively over time after exposure. We compared the features of silicosis in four strains of inbred mice selected for common use or immunologic reactivity 16 weeks after aerosol inhalation exposure to crystalline cristobalite silica (70 mg/m3, 5 hours/day, 12 days). C3H/HeN mice demonstrated histopathological silicotic lesions and enlarged intrapulmonary lymphoid tissue, and increased lung wet weight, bronchoalveolar lavage (BAL) recovery of macrophages, lymphocytes, and neutrophils, and total lung collagen (hydroxyproline). BALB/c mice developed slight pulmonary lesions; MRL/MpJ mice demonstrated prominent pulmonary infiltrates with lymphocytes; New Zealand Black mice developed extensive alveolar proteinaceous deposits, inflammation, and fibrosis. Our findings demonstrate orderly dose-time-response relationships, and a substantial variation of responses among inbred strains of mice. This model should prove valuable for future experimental interventions into the mechanisms of silicosis.

Amplification of the c-erb B-2 oncogene and prognosis of breast adenocarcinoma.

Fifty patients with typical infiltrating ductal adenocarcinoma of the breast were studied for amplification of the c-erb B-2 (neu/HER-2) oncogene within the tumor DNA. Amplification, ranging from 4 to greater than 50 copies per cell, was observed in 17 (34%) of the samples. The presence of c-erb B-2 gene amplification was not significantly correlated with patient survival, metastases, recurrence, or overall histologic grade. However, amplification was significantly associated with increased mitotic activity. Also, amplification of c-erb B-2 showed a significantly negative association with both progesterone and estrogen receptor presence. Progesterone receptor presence correlated significantly with survival.

Standardization of the surgical pathology report: formats, templates, and synoptic reports.

The most important routine vehicle for communication in surgical pathology is the specimen report. Although accuracy, clarity and thoroughness are the main goals, significant variability in format and content exists. In an effort to make reports more consistent, several mechanisms are useful and amenable for use in a computerized environment. These include templates, checklists, and tabular data reporting in the form of so-called synoptic reports. Such mechanisms are designed to ensure that critical information can be obtained consistently and easily from the report regardless of the institution of origin. Standardization is most easily extended to specific types of specimens, such as those resulting from mastectomies or colectomies with malignant neoplasms. The ultimate goal of the mechanisms discussed herein is to attain uniformity and consistency of included data found to be relevant to clinical management of patients.

Cytologic diagnosis of liver fluke infestation in a patient with subsequently documented cholangiocarcinoma.

In a 32-year-old Laotian immigrant who presented with a two-day history of vomiting, abdominal pain and jaundice, ultrasound examination revealed a posthepatic obstruction. Characteristic parasitic ova were present in bile fluid submitted for cytologic evaluation. Subsequent biopsy of the patient's bile duct lesion revealed a coexistent cholangiocarcinoma. The life cycles of Clonorchis sinensis and Ospisthorchis viverrini are reviewed along with the clinical and pathologic complications of infestation by these parasites in humans. The cytologic features of liver fluke infestation are characteristic and should be appreciated, as should the importance of its early diagnosis in the prevention of bile duct neoplasms.

Small airways diseases.

The histopathology of the small airways is frequently quite subtle, even in cases with clinically severe disease. In the present paper, we will demonstrate some recognizable straightforward pathological changes in the small airways, and also provide a list of clinico-pathological conditions that should be considered when each is encountered. In the second part of the paper, we will briefly overview some general histological patterns of lesions and specific diseases that may involve the small airways. The basic lesions will be subdivided into inflammatory (acute, chronic, granulomatous, with or without necrosis), proliferative (epithelial or mesenchymal), and remodeling reactions. Inflammatory and proliferative reactions may lead to a the third category of remodeling reactions, characterized by a variety of distortions of normal bronchiolar architecture, including occlusion, constriction, dilatation (with or without mucostasis), tortuosity and nodularity. In addition to this schematic distinction, it is important to recognize that these lesions are frequently combined together and evolve with one another. Each of the 3 reaction patterns may be exquisitely bronchiolar, or may extend in the surrounding parenchyma. In this case, it is important to distinguish between lesions that extend from the bronchiole to the parenchyma or vice versa (such as in organizing pneumonia patterns, where the main lesion is in the parenchyma). As most of these lesions are part of a dynamic process, it is important to recognize that a single causative agent may produce distinct pathologic features at different times in the natural history of the disease. In addition, the same clinical disease may result in a variety of pathologic lesions. Accordingly, there may be not always be an unequivocal relationship between the clinical disease/condition and specific histopathologic lesions in the small airways.