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.

Benign endobronchial mesenchymal tumors: their relationship to parenchymal pulmonary hamartomas.

The clinical and pathological data were reviewed on 17 patients with benign endobronchial mesenchymal tumors seen at the New England Deaconess Hospital between 1942 and 1981. The tumors were compared histologically to 147 intraparenchymal hamartomas studied during the same period. Thirteen tumors involved central bronchi and four occupied small, peripheral airways. These 17 lesions displayed overlapping histological features and ranged from predominantly cartilaginous to lipomatous growths. Mixtures of cartilage and other mesenchymal elements characterized 14 tumors, and adipose tissue was the principal component of three nonchondromatous growths. Both endobronchial and parenchymal tumors occurred predominantly during the fifth and sixth decades. Tumors of both groups contained similar mesenchymal constituents; however, the endobronchial lesions had fewer epithelial clefts, a decreased proportion of cartilage, and a correspondingly increased adipose tissue component. The centrally located intralumenal growths caused symptoms due to bronchial obstruction, while the four tumors within peripheral airways were usually symptomless, incidental findings. The histological similarity between the to groups and the presence of some endobronchial tumors within small, peripheral airways support the theory that endobronchial and parenchymal "hamartomas" are similar mesenchymal neoplasms of bronchial and bronchiolar walls occurring at different loci within the bronchial tree.

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.

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.

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.

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.

Respiratory tract pathology in patients with severe burns.

The histologic spectrum, pathogenesis, and clinical correlates of tracheobronchial and pulmonary lesions were studied by autopsy in six children and 27 adult burn victims. The burns covered a mean total body surface area of 57.7 +/- 23%. The mean survival time was 17.6 +/- 14.3 days. Patients over 60 years tended to survive longer than younger adults, but older patients had less extensive burns (P less than .01). Moderate or severe renal failure was an important clinical complication in 19 patients (58%). Diffuse alveolar damage (DAD) was observed in 16 patients, acute bronchopneumonia in seven patients, and necrotizing pneumonia in seven patients. Both DAD and pneumonia coexisted in 11 patients. Children most consistently developed pneumonia, 6 out of 6 versus 4 out of 17 younger adults (P less than .05). Factors which may have contributed to the pathogenesis of DAD included septicemia (12 patients), hypotension (nine patients), necrotizing pneumonia (six patients), and oxygen toxicity (four patients), in addition to the common presence of inhalational injury. The onset of DAD appeared late in eight patients with long survival periods, suggesting causal factors other than inhalational injury. However, survival rate did not differ in patients with or without DAD, and there was no correlation between DAD and the extent of burns. Airway lesions reflected the length of survival and showed the following sequence of changes: (1) mucosal necrosis and denudation, (2) acute inflammation and ulceration, and (3) squamous metaplasia. Endotracheal intubation injury and superinfection were confounding factors beyond the first few days of survival.

Mineral-associated hepatic injury: a report of seven cases with X-ray microanalysis.

The patterns of hepatic injury associated with various minerals were studied in seven patients. The subjects included one patient who was a sandblaster (silica by inhalation), one patient who was a dental laboratory technician (silica and chromium-cobalt alloy by inhalation), one patient with inhalational talcum powder abuse, and four chronic intravenous (IV) drug abusers (talc by IV injection). In all cases, the liver was examined by light and polarizing microscopy, and by scanning electron microscopy with energy-dispersive x-ray microanalysis. In the two patients with silica exposure, silica-containing sclerohyaline nodules were diffusely present in portal tracts and lobules. Both chromium-cobalt alloy and silica were present in the dental technician. In contrast, in all cases of talc exposure, aggregates of talc-laden macrophages were present in portal and centrilobular areas. Three IV drug abusers and the talcum powder abuser had histologic evidence of chronic hepatitis, most probably of viral etiology. We conclude that mineral type plays an important role in the pathogenesis and fibrogenesis of hepatic lesions. Compared with silica, talc primarily elicits a macrophage response without granuloma formation or fibrosis. Hepatic silicosis is a rare complication in dental laboratory technicians, and chromium-cobalt alloy may contribute to hepatic injury and fibrosis in this setting.

Longterm histopathologic follow-up of bronchial arteries after therapeutic embolization with polyvinyl alcohol (Ivalon) in patients with cystic fibrosis.

We used light microscopy to examine, at autopsy, bronchial arteries in three patients with cystic fibrosis who died, respectively, 10, 16, and 28 months after bronchial artery embolization with barium sulfate-impregnated polyvinyl alcohol (PVA) to control hemoptysis. PVA was not identified beyond the midsegmental bronchus in any patient. Persistent focal fibrovascular occlusion was noted in two patients, and recanalized and/or partially obstructed vessels were associated with PVA in all. The histologic reaction to PVA included fibrosis, mild chronic inflammation, localized foreign body reaction, and, in two patients, focal calcification of PVA spicules. Within the inflammatory milieu were numerous macrophages containing BaSO4. Extensive vascular mural destruction and fibrosis associated with PVA were also observed. Both PVA and BaSO4 were also frequently present in the perivascular connective tissue. These findings indicate that, although longterm occlusion persists after therapeutic arterial embolization with PVA, focal recanalization also occurs. The extent of vascular mural injury following PVA embolization in humans has been previously underestimated by animal experiments. Finally, perivascular deposition of PVA represents a common reaction to diverse foreign body emboli in both systemic and pulmonary arteries.

The pathology of fungal infection and colonization in patients with cystic fibrosis.

We used methenamine silver stains to retrospectively evaluate the prevalence of fungi and their associated inflammatory reactions in 63 patients with cystic fibrosis (CF) autopsied between 1982 and 1987. Fungi were detected in 13 patients (21%) who fell into three groups: respiratory tract colonization (five patients); localized infection (five patients); and disseminated infection (three patients). Hyphae consistent with Aspergillus sp were present in five patients; yeast-like cells and/or pseudohyphae consistent with Candida sp occurred in eight patients; and Histoplasma capsulatum produced fibrocaseous lymph node and splenic granulomas in one patient. Acute inflammation typified most fungal lesions, while bronchocentric granulomatosis affected one patient. Compared with patients with no fungi, those with fungi were more frequently treated with indwelling central venous catheters (P less than .05). Autopsy reports on 156 CF patients from 1964 to 1982 disclosed only one with disseminated mycosis (P less than .05). We conclude that stainable fungi can be found in CF patients at autopsy more frequently than previously realized. Fungi usually represent respiratory tract colonization or minimal localized infection, but the prevalence of fatal disseminated infection (4.8%) has also increased. Fungal infection in CF appears to be most closely associated with aggressive therapeutic intervention.

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.

Pulmonary air cysts in cystic fibrosis: relation of pathologic features to radiologic findings and history of pneumothorax.

One lung obtained from each of 21 consecutive autopsies in adolescents and young adults with cystic fibrosis was studied prospectively by macroscopic morphometry and light microscopy to determine the prevalence, morphology, and radiographic appearance of subpleural air cysts, which potentially contribute to spontaneous pneumothorax. In 15 lungs, 41 cysts of three anatomic types were identified: bronchiectatic cysts (23), interstitial cysts (13), and emphysematous bullae (5). All cysts were significantly more numerous in the upper lobe. Bronchiectatic cysts had the largest mean diameter, occupied from less than 1 per cent to 47.7 per cent of upper lobe volume in nine patients, and produced large multiloculated hyperlucencies on chest radiographs in five cases. All six lungs with prior pneumothorax contained at least one cyst, but no significant difference was found in the type or proportion of lung volume occupied by cysts between lungs with and without pneumothorax. Patients with large cysts had significantly lower chest radiograph scores, but there was no correlation between the proportion of lung volume occupied by cysts and patient age or duration of either symptomatic lung disease or colonization by bacteria. On chest radiographs only bronchiectatic cysts with conglomerate diameters of greater than 3 cm were visible. Smaller lesions could not be separated from ring shadows produced by bronchiectasis.

Shrinking pleuritis with lobar atelectasis, a morphologic variant of "round atelectasis".

Round atelectasis (shrinking pleuritis) is typically a localized process characterized by focal pleural scarring and subjacent peripheral atelectasis. We report three patients, studied at autopsy, with an unusual variant of round atelectasis, termed shrinking pleuritis with lobar atelectasis, which is characterized by lobar atelectasis, visceral pleural fibrosis involving multiple lobes, interlobar fibrous cords, pleural effusion, and nonspecific, persistent infiltrates on chest radiogram. The possible causes of shrinking pleuritis with lobar atelectasis in our patients were multiple and included environmental dust exposure, infection, uremia, and recurrent pleural effusions. Our findings support both the folding (pleural effusion) and fibrosing (pleural injury) theories of pathogenesis of round atelectasis and emphasize the spectrum of morphologic variability in this condition.

Mixed small cell and non-small cell lung cancer.

Seventeen (10 percent) of 176 patients with small-cell carcinoma of the lung seen at this hospital since 1976 proved to have mixed small-cell and non-small-cell tumors. The presence of a mixed lung cancer was established prior to chemotherapy or irradiation in nine patients. Eight were initially diagnosed as pure small-cell carcinoma but proved to have a mixed tumor at either surgery or autopsy. Of the 17 patients, eight received chemotherapy, and four had a partial response. Six of the 40 autopsies performed on patients with small-cell lung cancer demonstrated intrathoracic tumor which was histologically mixed. Extrathoracic metastases in these patients were heterogeneous and included pure small-cell, pure non-small-cell, and mixed histologic type. We conclude that mixed small-cell and non-small-cell lung cancers are relatively frequent and carry important prognostic and therapeutic implications. Clinical management of patients with small-cell lung cancer should therefore be flexible and tailored to the potential for histologic diversity. Mixed lung cancer in previously untreated patients suggests a common endodermal origin for small-cell and non-small-cell pulmonary tumors.

Complications of right heart catheterization. A prospective autopsy study.

The purpose of this study was to characterize the type and prevalence of abnormalities associated with right heart catheterization. We performed detailed post-mortem examinations of 32 consecutive patients brought to autopsy with a right heart catheter in the pulmonary artery. Thrombosis (17 patients, 53 percent), hemorrhagic lesions (25 patients, 78 percent), and intimal fibrin deposition (21 patients, 66 percent) were found at sites along the entire path of the catheter. Twenty-nine patients (91 percent) had either thrombosis, hemorrhage or both. While the superior vena cava was the most common site for all lesions, seven patients had thrombosis involving the chambers and valves of the heart and four had thrombosis involving the pulmonary artery. The incidence of thrombosis was significantly higher after 36 hours of catheterization (p less than 0.05). All five patients with thromboemboli in the more proximal pulmonary arteries had catheter-related thrombosis. We conclude that there is a high prevalence of thrombotic and hemorrhagic lesions in patients dying with pulmonary catheters in place; that the risk of thrombotic complications increases with duration of catheterization; and that patients with catheter-related thrombosis are at increased risk of thromboemboli to the proximal pulmonary arteries.

Pulmonary lymphoid neoplasms. Role of immunohistology in the study of cellular immunotypes and in differential diagnosis.

Seven cases of lymphoid neoplasms presenting in the lung were evaluated by immunohistology for T and B cell antigens and immunoglobulin light chains in frozen tissue sections. Although follow-up was short or inconclusive in some patients with lymphoma and pseudolymphoma, it was concluded that evaluation of T and B cell antigens and immunoglobulin light chains in frozen tissue is helpful in classifying lymphocytic neoplasms, especially in cases without definite cytologic evidence of malignancy. As demonstrated in two additional cases, lymphocyte/leukocyte markers in paraffin-embedded tissue are important in the differential diagnosis of lesions with cytologic features of malignancy.

Candida-associated renal papillary necrosis.

An autopsy series of 42 patients who had visceral candidiasis was studied to determine the incidence and clinicopathologic features of Candida-associated renal papillary necrosis. Papillary necrosis was found in nine patients (21%), associated in all instances with fungal invasion of the kidney. The single most common associated condition was prematurity, present in three neonates, and antibiotic or immunosuppressive therapy was a contributing factor in most instances. The clinical significance of candidal papillary necrosis is unclear because most patients had other causes of renal failure. Antemortem diagnosis is exceptionally difficult and had not been made in any of these patients. Pyelograms have aided in the diagnosis in only one well-documented case in the literature. This study shows that the pathologic features of candidal renal papillary necrosis correlate well with the findings in experimentally induced disease, and that this lesion appears to be more common than previously suspected.

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.

Regional alveolar damage (RAD). A localized counterpart of diffuse alveolar damage.

Diffuse alveolar damage (DAD) is usually considered a generalized lung process. During five years the authors observed 83 patients with generalized DAD in 827 adult autopsies (10.1%) and 10 patients with identical, but localized, lesions. The authors propose the term regional alveolar damage (RAD) to designate localized "DAD." RAD was unilateral in six patients and most frequently involved the upper lobe. All ten patients had chronic systemic diseases and presented with life-threatening illnesses. The probable causes of RAD were multifactorial and included hypotensive shock, septicemia, pneumonia, hyperoxia, and pancreatitis. All patients developed respiratory failure, requiring supplemental oxygen and, in nine patients, mechanical ventilation. Chest roentgenograms revealed alveolar or combined alveolar and interstitial infiltrates that corresponded to the lesions found at autopsy. The reasons for localization of RAD within the lung are unclear, but the presence of proliferative lesions and frequent involvement of the upper lobe suggests that RAD is not simply an early phase of DAD and implicates additional pathogenetic factors.