Disordered Toll-like receptor 2 responses in the pathogenesis of pulmonary sarcoidosis.

In this study, we hypothesized that the granulomatous disorder sarcoidosis is not caused by a single pathogen, but rather results from abnormal responses of Toll-like receptors (TLRs) to conserved bacterial elements. Unsorted bronchoalveolar lavage (BAL) cells from patients with suspected pulmonary sarcoidosis and healthy non-smoking control subjects were stimulated with representative ligands of TLR-2 (in both TLR-2/1 and TLR-2/6 heterodimers) and TLR-4. Responses were determined by assessing resulting production of tumour necrosis factor (TNF)-α and interleukin (IL)-6. BAL cells from patients in whom sarcoidosis was confirmed displayed increased cytokine responses to the TLR-2/1 ligand 19-kDa lipoprotein of Mycobacterium tuberculosis (LpqH) and decreased responses to the TLR-2/6 agonist fibroblast stimulating ligand-1 (FSL)-1. Subsequently, we evaluated the impact of TLR-2 gene deletion in a recently described murine model of T helper type 1 (Th1)-associated lung disease induced by heat-killed Propionibacterium acnes. As quantified by blinded scoring of lung pathology, P. acnes-induced granulomatous pulmonary inflammation was markedly attenuated in TLR-2(-/-) mice compared to wild-type C57BL/6 animals. The findings support a potential role for disordered TLR-2 responses in the pathogenesis of pulmonary sarcoidosis.

Surfactant protein deficiency in familial interstitial lung disease.

OBJECTIVE: To determine the contribution of surfactant protein abnormalities to the development of chronic lung injury in a familial form of interstitial lung disease. STUDY DESIGN: An 11-year-old girl, her sister, and their mother who were diagnosed with chronic interstitial lung disease underwent laboratory investigation of surfactant protein expression in bronchoalveolar lavage fluid and lung biopsy specimens. Nineteen patients with idiopathic pulmonary fibrosis and 9 patients who were investigated for pulmonary malignancy but who did not have interstitial lung disease served as control subjects. RESULTS: The 3 family members were found to have absent surfactant protein C (SP-C) and decreased levels of SP-A and SP-B in bronchoalveolar lavage fluid (BALF). Immunostaining for pulmonary surfactant proteins in lung biopsy specimens obtained from both children demonstrated a marked decrease of pro-SP-C in the alveolar epithelial cells but strong staining for pro-SP-B, SP-B, SP-A, and SP-D. No deviations from published surfactant protein B or C coding sequences were identified by DNA sequence analysis. All control subjects had a detectable level of SP-C in the BALF. CONCLUSION: The apparent absence of SP-C and a decrease in the levels of SP-A and SP-B are associated with familial interstitial lung disease.

Pulmonary pathology of acute respiratory distress syndrome.

Lung morphology in ARDS reflects the rapid evolution from interstitial and alveolar edema to end-stage fibrosis consequent to injury of the alveolocapillary unit. This morphologic progression, termed diffuse alveolar damage, has been subdivided into sequentially occurring exudative, proliferative, and fibrotic phases. Pulmonary lesions correlate with the phase of alveolar damage rather than its specific cause. The pathologic features are consistent with the effects of a host of injurious stimuli and the complex interaction of inflammatory mediators on alveolar epithelial and capillary endothelial cells. Although ARDS frequently culminates in "interstitial" fibrosis, the organization of intraluminal exudate dominates the histologic picture in the proliferative phase and establishes the framework for subsequent fibrous remodeling of the lung. Involvement of the pulmonary vasculature is an important aspect of ARDS, from the initial phase of edema to the terminal stage of intractable pulmonary hypertension. Vascular lesions include thrombotic, fibroproliferative, and obliterative changes that, like the parenchymal lesions, correlate with the temporal phase of DAD. Although ARDS is characterized by extensive bilateral lung involvement, alveolar damage can also affect the lung in a localized fashion. RAD is associated with the same clinical risk factors as DAD, suggesting that there is a spectrum in the extent of lung involvement and disease severity in patients at risk for ARDS. The factors that govern which patients will develop the fulminant syndrome are poorly understood. It must be re-emphasized that the lung is stereotyped in its response to injury and, consequently, descriptive, or even quantitative, studies of lung morphology can only provide clues regarding the initiating factors and pathogenetic mechanisms of ARDS. Progress in understanding the pathogenesis of ARDS and development of rational approaches to therapy will ultimately depend on careful clinical and experimental studies and the application of immunohistochemical and molecular biology techniques to unravel basic mechanisms of cellular injury and response.

Peripheral blood eosinophilia in association with sarcoidosis.

OBJECTIVES: To review retrospectively our experience with peripheral blood eosinophilia (PBE) in sarcoidosis and to analyze histologically lung biopsy specimens for the presence of lung tissue eosinophils. PATIENTS AND METHODS: We reviewed 140 cases of sarcoidosis diagnosed between May 1975 and January 1998. Ninety-five patients (66.3% women; 70.5% African American; mean age, 35.9 years) met the inclusion criteria. Transbronchial biopsy specimens from 82 patients were divided into 4 morphologic compartments: parenchyma, bronchial wall, parenchymal granulomas, and bronchial wall granulomas. Within compartments, up to 10 high-power fields were scored semiquantitatively for eosinophils, from 0 (none) to 4+ (numerous). RESULTS: Thirty-nine patients (41%) had PBE. Four had PBE greater than 10%. The highest eosinophil count (21%) occurred in 1 patient. Sixty-five (79%) of 82 patients had no or few (1+) eosinophils in lung tissue; 17 patients had eosinophils scored as 2+ or higher. There was no correlation between peripheral blood eosinophil count and presence of eosinophils in transbronchial biopsy specimens. Eosinophils were least conspicuous in parenchyma but evenly distributed in bronchial wall and parenchymal and bronchial wall granulomas. CONCLUSIONS: Peripheral blood eosinophilia occurs frequently in sarcoidosis. However, there appears to be no association between peripheral blood eosinophil count and presence of lung tissue eosinophils. Whether eosinophils participate in the pathogenesis of sarcoidosis requires further study.

Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature.

Cholestasis has been reported as a rare presentation among patients with severe liver injury secondary to amiodarone hepatic toxicity. We report an unusual case of amiodarone-induced cholestatic hepatotoxicity occurring after amiodarone had been discontinued and the initial abnormal liver function findings had improved. The patient, without jaundice at the initial presentation, developed severe jaundice about 4 months after withdrawal of amiodarone. Light and transmission electron microscopic examination of a specimen secured by computed tomographically guided liver biopsy was consistent with amiodarone hepatic toxicity as the cause of intrahepatic cholestasis. An abdominal ultrasound, endoscopic retrograde cholangiography, and dimethyl iminodiacetic acid and computed tomographic scans of the abdomen all failed to demonstrate any other causes for jaundice other than amiodarone toxicity. Thus, amiodarone hepatic toxicity may occur after drug withdrawal even if results of liver function tests improve. Histopathologic examination of a liver biopsy specimen is of value for diagnosis and prognosis. The liver biopsy findings, clinical course, and liver function test results are discussed, and the English-language literature on amiodarone cholestatic hepatotoxicity is reviewed.

Obliterative central bronchitis due to mineral dust in patients with pneumoconiosis.

OBJECTIVE: We studied at autopsy a distinctive obliterative bronchitis in three persons with pneumoconiosis and hilar node fibrosis. METHODS: Lungs were evaluated macroscopically, microscopically, and with energy-dispersive spectroscopy. RESULTS: Chest roentgenogram demonstrated right middle lobe syndrome in one patient; bronchostenosis was seen at bronchoscopy in another. The stenotic sites were in perihilar bronchi and showed an upper lobe predominance. Fibrosis with silicotic nodules involved the bronchus, peribronchial tissue, and adjacent lymph nodes. Simple coalworkers' pneumoconiosis was observed in two patients; the third had complicated, mixed dust fibrosis. CONCLUSION: Obliterative bronchitis represents an unusual fibrotic response to free crystalline silica. The process may occur simultaneously in the adjacent lymph node and the bronchial wall; however, it need not be associated with complicated pneumoconiosis. Clinically, obliterative bronchitis may masquerade as bronchogenic carcinoma.

Destruction and loss of bronchial cartilage in cystic fibrosis.

We studied by means of serial sections of intact isolated bronchi, the distribution and morphology of bronchial cartilage in lobar and segmental airways of 6 patients with cystic fibrosis (CF). Findings were compared to those of 4 young adults without CF who served as controls. Compared to the controls, cartilage in CF airways extended for a shorter absolute distance along the bronchial tree and disappeared at a more proximal branching level. Loss of cartilage appeared to correlate with the severity of bronchiectasis. In proximal airways chronic inflammation, destruction and fibrous replacement of cartilage preceded its disappearance. Immunohistochemical staining indicated that cells of monocyte/macrophage lineage (CD68, MAC387 positive) were most closely associated with chondrolysis. Dystrophic calcification and ossification were more commonly seen in CF bronchi and dystrophic calcification was present even in the lobar branches. Destruction of bronchial cartilage is the result of sustained bronchial infection and chronic inflammation and is an additional contributory factor to bronchiectasis and airway instability in patients with CF.

Cardiopulmonary pathology in patients with sleep apnea/obesity hypoventilation syndrome.

We reviewed clinical data, autopsy reports, and microscopic slides on 10 patients with sleep apnea/obesity hypoventilation syndrome (SA/OHS) to define the cardiopulmonary pathological features and establish clinicopathologic correlations. Ten obese (>136 kg) patients without SA/OHS were studied as controls. Patients with SA/OHS exhibited biventricular cardiac failure and pulmonary hypertension with a higher prevalence of moderate/severe pulmonary hemosiderosis (8 v 0 patients), alveolar hemorrhage (7 v 4 patients), capillary proliferation (4 v 0 patients), iron encrustation of elastica (1 v 0 patients) and medial hypertrophy of muscular pulmonary arteries (11.9 +/- 2.4 v 9.7 +/- 1.6%) (P < .05). In two patients capillary proliferation resembled capillary hemangiomatosis. Mean right ventricular thickness was higher in the SA/OHS group (0.71 +/- 0.17 v 0.42 +/- 0.1 cm) (P < .01). Four patients with SA/OHS and three controls had moderate/severe myocardial fibrosis. Biventricular cardiac failure caused death in seven patients with SA/OHS. Hypoxia is probably the most important cause of pulmonary hypertension, arterial muscularization, and right ventricular hypertrophy in SA/ OHS. Left ventricular failure in some SA/OHS patients may be the result of hypertensive cardiac disease. In others, the etiology of left ventricular failure was not determined morphologically, suggesting functional abnormalities related to obesity and/or apneic episodes.

Pulmonary intralobar sequestration in a patient with cystic fibrosis.

We report a case in which pulmonary Intralobar Sequestration (ILS) was an incidental finding at autopsy in an adult with Cystic Fibrosis. Two aberrant arteries from the descending thoracic aorta supplied a bronchial cystic lesion in the right lower lobe. Termination of the segmental bronchus and scar formation proximal to the cyst suggested prior bronchial obliteration. The elastic configuration of the aberrant aortic-derived vessels of the sequestration contrasted sharply with massively hypertrophied, muscular, bronchial arteries which supplied the bronchiectatic upper lobe. Sections of inferior pulmonary ligament were studied in five additional patients with CF but without ILS. Small muscular arteries were consistently noted within the inferior pulmonary ligament. These histologic findings support the concept that the vascular portion of ILS is congenital, whereas the bronchocystic component, in some cases, may be acquired.

Nontuberculous mycobacteria in cystic fibrosis. An autopsy study.

We retrospectively studied lung and hilar lymph nodes at autopsy in 18 patients with cystic fibrosis (CF) who had antemortem sputum cultures positive for nontuberculous mycobacteria (NTM). Histologic features were compared with those of 18 patients with CF who had negative antemortem cultures. The most frequent species isolated was M. chelonae group (10 patients). Multiple cultures were positive for NTM in six patients. Three patients were clinically considered to be infected, and two received antimycobacteria drugs. Necrotizing pulmonary granulomas associated with granulomatous organizing pneumonia were found at autopsy in two patients, each of whom had multiple positive sputum cultures and clinical evidence of infection. In one of these, mycobacterial infection was considered to be an important factor in her terminal illness. Neither necrotizing granulomas nor granulomatous organizing pneumonia were seen in the lung tissue of patients whose antemortem cultures were negative for mycobacteria. There was no difference in the prevalence of other granuloma-like lesions between those with and those without positive sputum cultures. No mycobacteria-related granulomas occurred in hilar lymph nodes, although histoplasma granulomas involved hilar lymph nodes of three patients. We conclude that granulomatous mycobacterial lung disease is present in a minority of patients (two of six patients in this study) who have multiple positive cultures. Histologic evidence of infection was not found in patients who had only one of multiple sputum cultures positive for NTM.

Histologic, microbiologic, and clinical correlates of the diagnosis of sarcoidosis by transbronchial biopsy.

OBJECTIVE: To determine the frequency of positive microbiologic cultures in patients with epithelioid granulomas and negative histochemical stains for microorganisms in transbronchial biopsy specimens. Secondary objectives were to compare the histologic features of sarcoidosis with those of infectious granulomas and to assess the reliability of histology in establishing the diagnosis of sarcoidosis. DESIGN: Retrospective study. Specific histologic features of transbronchial biopsy specimens were correlated with clinical and microbiologic data, final diagnosis, and an estimate of the probability, on admission, that the patient had sarcoidosis. SETTING: A large, urban, tertiary-care, university-affiliated hospital. PATIENTS: Ninety-two adult patients in whom epithelioid granulomas, negative for microorganisms on Ziehl-Neelsen and Gomori methemaine silver stain, were found in transbronchial biopsy specimens. Patients were identified through a search of surgical pathology files from 1975 to 1987. RESULTS: Ten patients (10.9%) had mycobacterial or fungal granulomas, while 82 had sarcoidosis. In all patients with a high clinical probability of sarcoidosis, the diagnosis was confirmed. Transbronchial biopsy specimens from patients with infectious granulomas had fewer granulomas (2.0 +/- 1.7 (SD) versus 7.1 +/- 6.6; P<.01), which involved a smaller proportion of lung tissue per case (9.5 +/- 10.0% versus 26.6 +/- 24.0%; P<.01). Sarcoid granulomas often exhibited Schaumann bodies (69.5% versus 10%; P<.01). Necrosis tended to predominate in infectious granulomas (19.5 versus 40%; not significant). CONCLUSIONS: Numerous granulomas, Schaumann bodies, and a high clinical probability of sarcoidosis are significantly associated with that diagnosis. Necrosis does not exclude sarcoidosis. Clinicopathologic assessment of transbronchial biopsy specimens is useful in predicting the final diagnosis of sarcoidosis but does not obviate the need for microbiologic cultures, which were positive in 10.9% of patients in this study.

Pulmonary disease due to infection by Mycobacterium avium complex in patients with AIDS.

We reviewed the clinical, radiographic, and histologic features of nine patients with AIDS and pulmonary disease due to Mycobacterium avium complex (MAC). Pulmonary MAC disease was defined by (1) the isolation of MAC from two or more lower respiratory tract specimens or from a single lung biopsy sample, (2) an infiltrate revealed by chest radiography, and (3) the absence of other identified pulmonary pathogens or malignancies. Pulmonary MAC disease was present in five (2.5%) of 200 patients with disseminated MAC infection and in four additional patients without evidence of dissemination, as assessed by blood culture. The median CD4 cell count at the time of presentation was 90/microL. Pulmonary MAC disease was the initial AIDS-defining infection in five patients and presented within a median of 5 months after the initial infection in four patients. Radiographic patterns for these nine patients included consolidating or nodular infiltrates and cavitation. The histopathology of pulmonary MAC disease was characterized by granulomatous inflammation, often associated with necrosis and few evident organisms. The conditions of all patients treated with multidrug regimens clinically improved.

Composite cutaneous T-cell lymphoma and small B-cell lymphocytic lymphoma: morphologic, immunologic, and molecular genetic documentation of concurrent lymph node involvement.

Synchronous cutaneous T-cell lymphoma and low-grade B-cell lymphoproliferative disorders have rarely been reported in the same patient. Coexpression of each phenotype in the same lymph node has not, to our knowledge, been previously documented. We describe an 86-year-old man with chronic pruritus and erythroderma and recent-onset peripheral lymphadenopathy and lymphocytosis. Lymph node biopsy provided morphological and immunohistochemical evidence of concurrent small B lymphocytic lymphoma and small pleomorphic T-cell lymphoma. Immunophenotyping of nodal lymphocytes demonstrated two distinct clones: IgM-kappa B-cells with CD5 positivity and CD7 negative T-helper cells. Both immunoglobulin (heavy and light chains) and T-cell receptor (beta I and beta II) gene rearrangements were detected by Southern blot analysis of the lymph node. In contrast, the immunophenotype of lymphocytes from peripheral blood and bone marrow was exclusively that of T-helper cells with atypical CD7 deletion. Electron microscopic examination of circulating lymphocytes revealed small cerebriform Sezary cells. This case demonstrates that small lymphocytic lymphoma may coexist intranodally with cutaneous T-cell lymphoma as a unique form of composite T- and B-cell lymphoma.

Transbronchial biopsy in patients with pulmonary eosinophilic granuloma. Comparison with findings on open lung biopsy.

We evaluated the findings on transbronchial biopsy specimens in reference to open lung biopsy specimens from 12 patients with pulmonary eosinophilic granuloma. Features in transbronchial biopsy specimens were further contrasted to those of patients with interstitial fibrosis and nondiagnostic biopsy specimens for localized lesions. Transbronchial biopsy specimens were randomized and graded for histologic features and cellularity. Patients with eosinophilic granuloma had more macrophages (P < .05) but equivalent numbers of eosinophils, neutrophils, and Langerhans' cells compared with those of the other two groups. Only two endoscopic biopsy specimens were histologically diagnostic or highly consistent with eosinophilic granuloma. We conclude that the diagnosis of eosinophilic granuloma is possible on transbronchial biopsy but requires a high index of suspicion. The demonstration of Langerhans' cells by immunohistochemical staining for S100 protein is a useful adjunct. The low diagnostic yield for eosinophilic granuloma on transbronchial biopsy results from inadequate sampling and from the nonspecific appearance of discrete lesions in small tissue samples.

Endobronchial adenocarcinoma with endometrioid features and prominent neuroendocrine differentiation. A variant of fetal adenocarcinoma.

An endobronchial tumor, resected from a 77-year-old man, had an endometrioid histologic pattern consistent with fetal adenocarcinoma. A distinctive feature of the neoplasm was prominent neuroendocrine differentiation, including single, discrete neuroendocrine cells; aggregates of neuroendocrine cells resembling miniature carcinoid tumors; and a single focus of undifferentiated small cell carcinoma. Immunohistochemical staining of neuroendocrine cells revealed the presence of neuron-specific enolase, chromogranin, somatostatin, insulin, and serotonin. The heterogeneous cell populations caused problems in differential diagnosis and histologic classification. This case demonstrates that fetal adenocarcinoma may occur as a central endobronchial mass and express a variable degree of neuroendocrine differentiation.

Invasive cavitary pulmonary aspergillosis in patients with cancer: a clinicopathologic study.

We studied the histopathology and clinicopathologic correlates of invasive cavitary pulmonary aspergillosis in 11 immunosuppressed patients with disseminated malignancy. In most patients cavities were produced by separation of necrotic from viable lung, resulting in an intracavitary sequestrum ("lung ball"). Central dissolution of large necrotic areas and suppurative granulomatous aspergillary pneumonia were additional causes of cavities in three patients. In four patients with chronic cavities sequestra had been replaced by intracavitary mycetomas ("fungus balls"). Neutrophils usually were numerous at the interface of the sequestrum and adjacent lung, but were minimally present in three patients with prolonged severe neutropenia. The lack of neutrophils in some patients suggests that factors other than neutrophil-derived proteases may be important in cavity formation. A prominent giant cell reaction was seen in three patients with chronic cavities. Hemoptysis occurred in five patients and massive hemoptysis due to a bronchoarterial fistula caused the death of one patient. The "air-crescent" sign was not observed radiographically in any patient and is therefore considered to be an insensitive marker for lung cavitation in invasive aspergillosis. Persistent intracavitary fungal growth may serve as a reservoir for recurrent fungal invasion in patients with prolonged or repeated episodes of severe neutropenia.

Reactive eosinophilic pulmonary vascular infiltration in patients with spontaneous pneumothorax.

Prominent nonnecrotizing eosinophilic inflammation of muscular pulmonary arteries was seen in resected lung tissue from two patients with spontaneous pneumothorax. Other histologic features included reactive eosinophilic pleuritis (REP) and fibrobullous disease. Eosinophilic vascular infiltration was not contiguous to REP. In neither patient was there a specific and recognized cause of eosinophilic vasculitis. Both patients are without pulmonary symptoms 1 and 4 years after pneumothorax. Eosinophilic vascular infiltration initially suggested the diagnosis of allergic angiitis or pulmonary eosinophilic granuloma. These diagnoses were excluded by clinical and morphologic data. We subsequently reviewed 30 cases of lung tissue resected from patients with pneumothorax and found REP in 18 patients (60%) and mild pulmonary vascular and perivascular eosinophilia in five patients (17%). REP was present in all cases with eosinophilic vascular infiltration. We conclude that this eosinophilic vascular lesion is an unusual reaction in patients with REP and pneumothorax. Occasionally this lesion mimics allergic angiitis or eosinophilic granuloma. The pathogenesis is probably related to vascular transport of eosinophils to the injured pleural surface.

Mineralizing pulmonary elastosis in chronic cardiac failure. "Endogenous pneumoconiosis" revisited.

The histopathology, ultrastructure, and clinicopathologic correlations in six patients with cardiac failure and iron encrustation of lung elastic tissue were examined at autopsy. Transmission electron microscopy (TEM) and energy dispersive x-ray analysis were applied to two cases. Of the group, five patients had cardiac failure due to systemic hypertension (4 patients), valvular disease (4 patients), or coronary atherosclerosis (4 patients). Biventricular failure in one patient was associated with sleep apnea. Both iron and calcium, identified by histochemical stains, impregnated degenerated alveolar and vascular elastic fibers and were associated with a foreign body reaction and focal interstitial fibrosis. Energy dispersive x-ray analysis and TEM demonstrated iron and calcium on the microfibrillar portion of elastin. Morphometry indicated vascular changes of pulmonary venous hypertension. The authors concluded that mineral deposition probably represents nonspecific precipitation of metallic ions on altered elastic fibers in patients with cardiac failure. "Mineralizing elastosis" potentially contributes to lung restriction and, occasionally, can be a source of diagnostic confusion.