Lymphatic manifestations of lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a slowly progressive, low grade, metastasizing neoplasm, associated with cellular invasion and cystic destruction of the pulmonary parenchyma. Although the source of LAM cells that infiltrate the lung is unknown, available evidence indicates that the disease spreads primarily through lymphatic channels, often involving abdominal, axial, and retroperitoneal nodes, suggestive of an origin in the pelvis. LAM cells harbor mutations in tuberous sclerosis genes and produce lymphangiogenic growth factors, which facilitate access to and movement through the lymphatic system and likely play an important role in destructive tissue remodeling in the lung. Lymphatic manifestations of LAM include thoracic duct wall invasion, lymphangioleiomyoma formation, chylous fluid collections in the peritoneal, pleural, and pericardial spaces, chyloptysis, chylocolporrheal chylometrorrhea, chyle leak from the umbilicus, chylous pulmonary congestion, and lower extremity lymphedema. LAM lesions express lymphangiogenic growth factors VEGF-C and VEGF-D; growth factor receptors, VEGFR-2 and VEGFR-3; and markers LYVE-1 and podoplanin, and are laced with chaotic lymphatic channels. Serum VEGF-D is elevated in 70% of patients with LAM and is a clinically useful diagnostic and prognostic biomarker. Molecular targeted therapy with sirolimus stabilizes lung function, is anti-lymphangiogenic, and is highly effective for the lymphatic and chylous complications of LAM. Future trials in patients with LAM who have lymphatic manifestations or elevated serum VEGF-D will likely focus on the VEGF-C/VEGF-D/VEGFR-3 axis.

Polymyxin-B hemoperfusion for acute exacerbation of idiopathic pulmonary fibrosis: serum IL-7 as a prognostic marker.

BACKGROUND: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) has an extremely poor prognosis. Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) has been used to improve oxygenation for acute respiratory distress syndrome. The study aim was to retrospectively determine the predictive factors affecting the prognosis of AE of IPF treated with PMX-DHP. METHODS: We studied patients suffering from AE of IPF, treated with PMX-DHP combined with high-dose corticosteroid therapy. Stored serum taken before and after PMX-DHP therapy was analyzed for 27 cytokines and chemokines. RESULTS: Nineteen patients with AE of IPF were studied. The median survival time after diagnosis of AE was 22 days. Survival rates after diagnosis of AE were 47.4% at 30 days, 31.6% at 60 days, and 26.3% at 90 days. Serum levels of Interleukin (IL)-7, an anti-fibrotic cytokine, in survivors at day 30 following PMX-DHP therapy ('Survivors') significantly increased after the treatment, compared to serum levels of non-survivors at day 30 after the therapy ('Nonsurvivors'), which did not demonstrate a significant change. Serum levels of IL-1beta, interferon-y and chemokine ligand (CCL) 2 levels were not significantly altered in 'Survivors', but were significantly changed in 'Nonsurvivors.' Multivariate Cox proportional-hazards analysis showed that an increase in IL-7 levels after PMX-DHP therapy and treatment without intubation (other than invasive positive-pressure ventilation) were significantly better prognostic factors. CONCLUSION: The results suggest that serum IL-7 may be a useful prognostic factor for patients with AE of IPF treated with PMX-DHP, possibly reflecting underlying anti-fibrotic mechanisms.

Risk factors of acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Although acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a well known clinical condition, predicting risk factors remain unknown. We evaluated the frequency, risk factors and impact on survival of AE-IPF. METHODS: We retrospectively studied patients diagnosed with IPF based on the criteria of the ATS/ERS consensus statement and followed them for periods of more than 3 years except in dead cases. Initial characteristics including the level of dyspnoea, which was assessed with the modified Medical Research Council (MRC) scale, and decline of forced vital capacity (FVC) defined by at least 10% decline at 6 months, were evaluated as possible risk factors for AE. RESULTS: Seventy-four patients with IPF were studied. One-year, two-year, and three-year incidence of AE were 8.6%, 12.6%, and 23.9%, respectively. Multivariate analysis revealed that higher body mass index (BMI) [hazard ratio (HR), 1.20; 95% confidence interval (CI), 1.03-1.40], higher modified MRC scale [HR, 2.93; 95% CI, 1.46-5.85], and a decline in FVC at 6 mounths [HR, 0.97-2.60 (per mo); 95% CI, 1.01-7.45] were independent risk factors for AE-IPF. The causes of death were assessed to be AE in 20 of 57 expired patients. A stepwise multivariate Cox regression model evaluating AE-IPF, adjusted for %FVC and decline in FVC, demonstrated a statistically significant impact on overall survival [HR, 2.79; 95% CI, 1.59-4.88; p < 0.001]. CONCLUSION: These data suggest that initial high modified MRC scale, high BMI, and decline in FVC at 6 months were significant independent risk factors for AE-IPF. AE was an independent prognostic factor in IPF.

Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia.

Most studies of idiopathic nonspecific interstitial pneumonia (NSIP) have primarily studied mortality. In order to clarify the detailed outcome and prognostic markers in idiopathic NSIP, the clinical course with initial radiological and clinical features was analysed. The clinical course of 83 patients who were classified with idiopathic NSIP (72 fibrotic, 11 cellular; 27 males and 56 females; mean+/-sd age 54.4+/-10.1 yrs) was retrospectively analysed. In fibrotic NSIP, 16 (22%) patients died of NSIP-related causes with a median (range) follow-up of 53 (0.3-181) months. Despite the favourable survival (5-yr 74%), patients with fibrotic NSIP were frequently hospitalised with recurrence rate of 36%. Reduced forced vital capacity at 12 months was a predictor of mortality. On follow-up, lung function was improved or stable in approximately 80% of the patients. The extent of consolidation and ground-glass opacity on initial high-resolution computed tomography correlated significantly with serial changes of lung function, and the presence of honeycombing was a predictor of poor prognosis. During follow-up, eight (10%) patients developed collagen vascular disease. In conclusion, the overall prognosis of fibrotic nonspecific interstitial pneumonia was good; however, there were significant recurrences despite initial improvement and a subset of the patients did not respond to therapy. Some patients developed collagen vascular diseases at a later date.

Long-term complications and prognosis of chronic beryllium disease.

BACKGROUND: Chronic beryllium disease (CBD) is a rare disease, and there are no previous reports that have followed CBD patients over several decades. Thus, the long-term complications and prognosis of this illness still remain unclear. OBJECTIVE: The aim of this study was to investigate long-term complications and prognosis of CBD patients. STUDY DESIGN AND METHODS: This was a retrospective study based on the medical records of all CBD patients diagnosed at Kyoto University Hospital between the period 1973 to the present day. Ultimately, ten patients whose diagnoses had been made during the period 1973 to 1977 were included. Long-term physiological and radiological change, complications and prognosis of these patients were investigated. RESULTS: Three patients completely remitted, and one died of cor-pulmonale. Among the remaining six patients, four have been followed up for more than thirty years in our institute. The majority developed mixed patterns of lung function impairment, cavity lesions of the lung, pneumothorax, and respiratory infections. CONCLUSIONS: Long-term prognosis of CBD was poor with several complications due to chronic parenchymal and airway lesions.

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.

Diffuse panbronchiolitis: diagnosis and distinction from various pulmonary diseases with centrilobular interstitial foam cell accumulations.

Diffuse panbronchiolitis (DPB) is a clinicopathologic entity characterized histologically by chronic inflammation principally affecting the respiratory bronchioles. Few pathologists outside Japan are familiar with this entity. The most distinctive pathologic feature of DPB is chronic inflammation and an accumulation of foam cells in the walls of the respiratory bronchioles, adjacent alveolar ducts, and alveoli (PB unit lesion). The differential diagnosis is important both clinically and histologically because of the similarity of DPB to other chronic airway diseases. We report seven cases of DPB and 20 examples of a histologically similar lesion (PB-like lesion) found in a large review of cases of bronchiolitis, cystic fibrosis, bronchiectasis, aspiration pneumonia, extrinsic allergic alveolitis. Wegener's granulomatosis, bronchocentric granulomatosis, and malignant lymphoma. The results indicate that the PB-like lesion is a nonspecific histologic finding; the diagnosis of DPB can be made only in the appropriate clinical setting and when other conditions have been carefully ruled out.

Differential diagnosis of bronchiolitis obliterans organizing pneumonia.

The disease concept of idiopathic BOOP has emerged from a study of many open lung biopsy cases of diffuse infiltrative lung disease. The histopathologic features of idiopathic BOOP have several components: bronchiolitis obliterans, organizing pneumonia, accumulation of foamy cells in the peripheral air spaces, and interstitial infiltration of mononuclear cells. These pathologic findings are nonspecific and many conditions show such a BOOP pattern. Idiopathic BOOP has been discussed in the context of bronchiolitis obliterans, organizing pneumonia, and interstitial pneumonia. While clinically idiopathic BOOP has a relatively broad spectrum of manifestation, BOOP stands as a clinicopathologic disease entity among diffuse infiltrative lung diseases of unknown etiology.

Bronchiolitis obliterans organizing pneumonia. Clinical features and differential diagnosis.

The clinical features of 34 Japanese patients with bronchiolitis obliterans organizing pneumonia (BOOP) are discussed. Thirty-two patients (94 percent) had symptoms of cough, fever, or dyspnea. On chest roentgenograms, bilateral patchy infiltrates were seen most frequently in 23 patients (68 percent), followed by small linear opacities in five (15 percent), both patchy infiltrates and reticulonodular opacities in four (12 percent), and reticulonodular opacities in two (6 percent). The bronchoalveolar lavage fluid (BALF) cell findings obtained from 26 patients revealed an increase in the percentage of lymphocytes in 20 patients (77 percent), neutrophils in 15 (58 percent), and eosinophils in 16 (62 percent), and a decrease in the CD4+/CD8+ ratio in 14 of 23 patients (61 percent). Corticosteroids were administered to 25 patients. Except for one patient who died, the prognosis was good in all patients. Further, in patients without corticosteroid therapy, the prognosis was good.

The diagnostic accuracy of high-resolution computed tomography in diffuse infiltrative lung diseases.

The purpose of this study was to evaluate the role of high-resolution computed tomography (HRCT) in the clinical diagnosis of diffuse infiltrative lung disease (DILD). Diagnostic accuracy was compared using both chest radiography and HRCT. One hundred thirty-four cases of DILD, representing 21 different diseases, were selected for study, and the disease state was confirmed either histologically or microbiologically. The HRCT images and chest radiographs, available in all cases, were reviewed separately and in random order by 20 physicians who were provided only with information on each patient's age and sex. Overall, a correct first-choice diagnosis was made in 38 percent using radiographs and in 46 percent using HRCT images (p < 0.01). The correct diagnosis was among the top three choices in 49 percent when chest radiographs were used, and in 59 percent when HRCT images were viewed (p < 0.01). The correct first-choice diagnosis increased remarkably when the HRCT was used in usual interstitial pneumonia, sarcoidosis, alveolar proteinosis, bronchiolitis obliterans organizing pneumonia, hypersensitivity pneumonitis, and pulmonary lymphangiomyomatosis. High-resolution computed tomography was confirmed to be superior to conventional radiography in the accurate diagnosis of DILD in clinical practice.

Proliferative characteristics of fibroblast lines derived from open lung biopsy specimens of patients with IPF (UIP).

We compared the doubling time of fibroblasts derived from idiopathic pulmonary fibrosis (usual interstitial pneumonia) (IPF [UIP]) lung tissues and control fibroblasts, cultured in usual growth medium, and examined the response of these fibroblasts to platelet-derived growth factor (PDGF) and prostaglandin E2 (PGE2). Ten fibroblast lines from open lung biopsy specimens of patients with IPF (UIP) and ten control fibroblast lines from surgically resected lung tissue of patients with limited lung diseases were established. The average doubling time of fibroblast lines was 32.0 +/- 6.0 h (mean +/- SD) in UIP and 33.2 +/- 10.4 h in controls, showing no difference between the two groups. To examine the responses of fibroblasts to PDGF and PGE2 and the differences between fibroblasts derived from fibrotic tissues with different intensity of fibrosis, lung specimens from five patients with IPF were subdivided into two groups, higher-intensity fibrotic lesions (H) and lower-intensity fibrotic lesions (L). The fibroblast lines were established separately. 3H-thymidine uptake with or without PDGF or PGE2 was examined. Results were expressed as the index of thymidine incorporation into the fibroblasts. There were no differences in the doubling times and the responses to PDGF and PGE2 between H and L. There were no differences between control and H regarding their response to PDGF. In response to PGE2, the growth inhibition for H was significantly decreased compared with the control (p less than 0.05). There was no difference in growth inhibition between H and L. The finding that PGE2 inhibits fibroblast proliferation less in UIP lung tissue suggests that fibroblasts from UIP were functionally altered cells or, to some extent, out of normal regulation. These results suggest an abnormal proliferation of fibroblasts observed in IPF (UIP).

Recurrent spontaneous pneumothoraces associated with juvenile polymyositis.

A 17-year-old man, who had received a diagnosis of juvenile polymyositis (PM) at the age of 1 year, developed recurrent spontaneous pneumothoraces and underwent surgical treatment by means of video-assisted thoracic surgery. Intraoperative observation and microscopic studies demonstrated numerous bleb-like lesions below the visceral pleura. To our knowledge, this is the first article that describes a case of spontaneous pneumothorax associated with PM. Our observation should lead to broadening of the spectrum of pleuropulmonary manifestations of PM.

Clubbing of the fingers and smooth-muscle proliferation in fibrotic changes in the lung in patients with idiopathic pulmonary fibrosis.

In our study of 52 patients with idiopathic pulmonary fibrosis (IPF), we found that the incidence of clubbing of the fingers was significantly more frequent in male than in female patients and in patients who showed lesser grades of honeycombing and higher grades of smooth-muscle proliferation in the pulmonary fibrotic changes (p < 0.01). Smooth-muscle proliferation in fibrotic changes of open lung biopsy specimens correlated with the mode of detection of IPF and the presence of clubbing of the fingers, duration of symptoms of the lower respiratory tract, and a higher extent of pulmonary infiltrates on chest radiographs (p < 0.05). However, the presence of clubbing of the fingers or grades of smooth-muscle proliferation in the pulmonary fibrotic changes did not correlate with the 2-year survival after open lung biopsy.

Multifocal micronodular pneumocyte hyperplasia in a postmenopausal woman with tuberous sclerosis.

We report a peculiar case of multifocal micronodular pneumocyte hyperplasia (MMPH) without association of pulmonary lymphangioleiomyomatosis (LAM) in a 56-year-old postmenopausal woman with tuberous sclerosis. This case is surmised to be a forme fruste of tuberous sclerosis. Computed tomography demonstrated multiple micronodules, measuring up to 5 mm in size, present in the bilateral lung fields, but no cystic changes. A proliferation of pleomorphic type-II pneumocytes lining the thickened alveolar septa in an adenomatoid pattern, with an associated increase in alveolar macrophages, was observed without typical nuclear atypia. In fully developed lesions, the ingrowth of more proliferating type-II pneumocytes into the thickened alveolar septa and macrophages filling the alveolar lumens were characteristic findings. Proliferation of immature smooth muscle cells suggesting LAM was not observed. Positive immunohistochemical stains for cytokeratin, epithelial membrane antigen, and surfactant apoproteins A and B, and negative staining for HMB45, alpha-1 smooth muscle actin, desmin, and carcinoembryonic antigen confirmed the characteristics of alveolar lining cells in each MMPH lesion. MMPH associated with tuberous sclerosis in the postmenopausal woman appears to be similar to that described in premenopausal women. The present case is familial rather than sporadic and suggests no relationship between the development of MMPH and the underlying hormonal state.

Immunohistochemical localization of surfactant apoproteins in usual interstitial pneumonia associated with pulmonary carcinoma.

Surfactant apoproteins A and B (SP-A and SP-B) are antigenic determinants of pulmonary surfactant complexes. The role and functional significance of these proteins are largely unknown and the pattern of expression is probably related to the functional maturation of type II pneumocytes. Differential expression of SP-A and SP-B was reported in the developing human lung but little is known of their expression in the chronic injury. We studied 5 surgical cases of usual interstitial pneumonia (UIP) associated with carcinoma to evaluate the expression of pulmonary surfactant apoproteins. These cases were immunohistochemically examined by the streptavidin-biotin complex method using monoclonal antibodies HS-1 and HS-2 against pulmonary surfactant apoprotein A (SP-A) and B (SP-B), respectively. In UIP, SP-B was expressed strongly in type II pneumocytes and Clara cells but bronchiolar epithelium and metaplastic squamous cell lines in the honeycomb lesion were non-reactive. SP-A showed a similar pattern but much weaker reactivity when compared to that of SP-B. Type II pneumocytes in normal lung tissue exhibited weak immunoreactivity and no difference in the intensity of staining between SP-A and SP-B. Neither carcinomatous area nor metaplastic lining cells at honeycomb lesion show immunoreactivity to SP-A and SP-B. These results suggest that type II pneumocytes in the UIP are functionally immature in their expression of the apoprotein types and the metaplastic squamous cells or neoplastic transformed cells do not have molecular characteristics of type II pneumocytes.

Facts and controversies in the classification of idiopathic interstitial pneumonias.

Idiopathic interstitial pneumonias are defined from the pathological point of view as non granulomatous intralobular inflammatory and fibrotic processes involving the alveolar walls. More than thirty years ago Liebow and Carrington pioneered the notion that morphological characteristics could be used with benefit in separating the different entities found in this group, which present with typical, but not pathognomonic clinical features. In the mid-1980s some entities, including giant cell interstitial pneumonia (GIP) and lymphocytic interstitial pneumonia (LIP), were removed from this group and considered as peculiar forms. In the early 90s the concept of cellular or nonspecific interstitial pneumonia was reconsidered, leading to an in depth revision of various types of interstitial pneumonia of unknown etiology. The histological pattern observed in patients with idiopathic pulmonary fibrosis is now referred to as usual interstitial pneumonia (UIP). Other entities that have been revised during the last ten years are desquamative interstitial pneumonia/alveolar macrophage pneumonia (DIP/AMP), respiratory bronchiolitis-interstitial lung disease (RB-ILD), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP) and nonspecific interstitial pneumonia (NSIP). This paper provides a detailed description of pulmonary disorders which have been included in the new classification systems of idiopathic interstitial pneumonias. In the second part of the paper we will discuss several doubts and controversies that this new classification schemes leave unresolved.

Hospital-based historical cohort study of 234 histologically proven Japanese patients with IPF.

BACKGROUND AND AIM OF THE WORK: Variable clinical courses have been recognized in patients with idiopathic pulmonary fibrosis (IPF), but the disease is known to have a fundamentally unfavorable outcome. In addition, we have yet to fully understand whether the regional or population differences are negligible or not. Therefore, we analyzed the clinical outcomes in Japanese IPF patients in a hospital-based historical cohort study. METHODS: A questionnaire was used to collect records for retrospective analysis of the IPF patients. We analyzed data collected from 51 hospitals and clinics in Japan on 234 Japanese IPF patients (males 170, females 64) with IPF who had been followed up after diagnosis. RESULTS: 1. Five and ten years after the detection of exertional dyspnea, the overall survival rates were 41.0% and 20.1%, respectively. A higher age at the time of detection (over 59) was related to a decrease in survival rates. 2. The incidence of complications was no higher in the corticosteroid-treated cases than in the untreated cases. The effects of corticosteroid treatment on survival was not confirmed in this type of study. CONCLUSIONS: The survival rates of histologically proven Japanese patients with IPF were similar to the rates previously reported in different populations. Age at the detection of exertional dyspnea was critical in terms of the survival rate.

Estimation of free calcium levels after thyroidectomy.

Total calcium is routinely measured after thyroidectomy in a clinical setting, while the measurement or calculation of the free calcium level is not generally performed. We reviewed total and free calcium levels in patients who underwent lobectomy (n = 15), subtotal thyroidectomy (n = 15) and total thyroidectomy (n = 15). Postoperative total calcium levels decreased significantly in comparison to preoperative levels in all thyroidectomies (p < 0.01), and this fall was significantly related to the extent of surgery (p < 0.01). In contrast, there was no significant difference between preoperative and postoperative free calcium levels in patients undergoing lobectomy, although we found a decrease in free calcium levels after both subtotal and total thyroidectomy. Total protein levels decreased regardless of the type of operation. Serum total calcium levels were thought to be altered by serum protein levels through the change of protein-bound calcium levels. When examined for free calcium levels, some patients were administered unnecessary calcium supplementation because hypocalcemia had been judged from the total calcium level. Since the wrong diagnosis may be given with regard to hypoparathyroidism by measurement of total calcium levels alone, we propose that free calcium levels should be routinely measured or calculated after thyroidectomy.

Diffuse lung disease: pathologic basis for the high-resolution computed tomography findings.

High-resolution computed tomography (HRCT) allows accurate assessment of the pattern and distribution of diffuse lung diseases. Optimal interpretation of the HRCT images requires understanding of some basic concepts of normal anatomy, as well as the pathologic basis for the HRCT findings in diffuse lung disease. This review summarizes our experience with over 400 radiologic-pathologic correlations in diffuse lung disease. These correlations include contact radiography with stereo views and stereomicroscopic images of lung specimens. We describe our technique to inflate and fix the lung specimens and illustrate normal and abnormal lung morphology.

Sarcoidosis with granulomatous interstitial nephritis: report of three cases.

Three cases of sarcoidosis with granulomatous interstitial nephritis are reported. Patients were all male and over 50 years of age. They simultaneously had evidence of multiorgan involvement of sarcoidosis including lung and skin and/or eye. In addition, distinct features were found in each case: a granulomatous infiltration mimicking unilateral renal tumor (case 1); renal insufficiency solely due to granulomatous interstitial nephritis (case 2); and renal insufficiency with calcemic nephropathy and granulomatous interstitial nephritis (case 3). Prednisolone therapy resulted in disappearance of the pseudotumor in case 1 and partial improvement of renal function in cases 2 and 3. In cases 2 and 3, however, plasma creatinine did not return to normal values and a second renal biopsy in case 2 demonstrated residual interstitial fibrosis and few granulomas, suggesting that steroid therapy did not achieve complete reversal of changes.