Stavros H. Constantopoulos

Lung involvement in primary Sjögren’s syndrome is mainly related to the small airway disease

OBJECTIVE To evaluate lung involvement in patients with primary Sjögren’s syndrome. METHODS Sixty one consecutive, non-smoking patients, 58 women and three men, were evaluated clinically, physiologically, and radiologically. A bronchial and/or transbronchial biopsy was performed on 13 of the patients. Physiological data were compared with that of a control group of 53 healthy non-smoking subjects matched for age and sex. RESULTS In 41% of the patients the main symptom was dry cough. Physiological studies revealed that the patients presented significantly lower expiratory flow values (% pred) when compared with those of the control group: the forced expiratory volume in one second (FEV1) (mean (SD)) was 96% (16) v 111% (13) (p<0.0001), the maximal expiratory flow at the 50% of the vital capacity (MEF50) was 72% (24) v103% (17) (p<0.0001), and the maximal expiratory flow at the 25% of the vital capacity (MEF25) was 49% (25)v 98 % (20) (p<0.0001). No significant difference was noted for the carbon monoxide diffusion value (% pred), between patients and controls. Blood gases were evaluated in 44 patients: mild hypoxemia was observed, and the alveolo-arterial oxygen difference (P(A-a)o 2) correlated significantly with MEF50 (r=0.35, p<0.01) and MEF25 (r=0.33, p<0.01) values. Chest radiography showed mild, interstitial-like changes in 27 patients while slightly increased markings were present in 21. High resolution computed tomography of the lungs was performed in 32 patients (four with a normal chest radiograph, six with suspected interstitial pattern, 19 with apparent interstitial pattern, and three with hyperinflation) and revealed predominantly wall thickening at the segmental bronchi. All positive findings by computed tomography derived from the patients with abnormal chest radiographs. Transbronchial and/or endobronchial biopsy specimens in 10 of the 11 sufficient tissue samples revealed peribronchial and/or peribronchiolar mononuclear inflammation, while interstitial inflammation coexisted in two patients. CONCLUSION The airway epithelia seem to be the main target of the inflammatory lesion of the lung in patients with primary Sjögren’s syndrome. It seems to be common, subclinically leading to obstructive small airway physiological abnormalities.

Endobronchial metastases secondary to solid tumors: report of eight cases and review of the literature

Endobronchial metastases (EBM) secondaries to extrapulmonary solid malignant tumors are rare. Breast, colon and renal adenocarcinomas are the most frequent tumors associated with EBM. Since 1990 we have treated eight patients with EBM secondary to renal adenocarcinoma (three cases), colon adenocarcinoma (two cases), gastric adenocarcinoma (one case), bladder carcinoma (one case) and basal cell carcinoma (one case). Endobronchial lesions were detected by bronchoscopy and their metastatic nature was confirmed histopathologically in all eight cases. We also conducted a review of EBM reporting studies published in English language. The median interval from the diagnosis of the primary tumour was 41 months. Symptoms and radiological findings were indistinguishable from those of primary lung cancer. Five patients were treated with external radiotherapy with symptomatic improvement while two patients had chemotherapy and one patient underwent surgical resection of the metastasis. Systemic treatment was used in six cases with no significant effect on EBM. Median survival after EBM diagnosis was 9 months with one patient surviving 3.5 years and two patients still alive at 1 year. In conclusion, EBM usually represent a late manifestation requiring differential diagnosis from a primary lung cancer. Local treatment may result in symptomatic improvement but prognosis is generally poor averaging 1-2 years in most series.

ASSOCIATION OF METSOVO LUNG AND PLEURAL MESOTHELIOMA WITH EXPOSURE TO TREMOLITE-CONTAINING WHITEWASH

Pleural thickening, bilateral pleural hyalinised plaques, and restrictive lung function are found among inhabitants of four small villages in northwestern Greece. Transbronchial biopsy samples from patients with disease contained tremolite fibres. Malignant pleural mesothelioma has now been reported in these villages and accounts for approximately 1% of the total mortality from 1981 to 1985. The principal whitewash once used in this area is predominantly asbestiform tremolite. The fibre is identical in every respect to fibres found in the lung tissues of people with Metsovo lung. The membrane activity of this tremolite is greater than that of the commercially used asbestiform amphiboles amosite and crocidolite. This measure of cytotoxicity lends further support to the hypothesis that this fibre is the agent of Metsovo lung and mesothelioma.

Imaging of thoracic Wegener's granulomatosis: The computed tomographic appearance

PURPOSE Computed tomography (CT) can play a major role in the examination of patients with diffuse infiltrative disorders of the lung. CT patterns of thoracic Wegeners granulomatosis were retrospectively evaluated in this study. The CT appearance was compared with imaging obtained by conventional plain roentgenograms. PATIENTS AND METHODS Fourteen patients with Wegeners granulomatosis seen during the last 5 years are described. Conventional chest roentgenograms and CT scans from these patients are reviewed. RESULTS The most frequent manifestation found in the lungs of patients with Wegeners granulomatosis was that of rounded opacities with or without cavitation. This was observed in 7 of 14 patients. Relatively unexpected was the frequent occurrence of bronchovascular bundle cuffing with a quite constant and characteristic bronchocentric distribution. This finding was observed in 5 of 14 patients. Vasculitis sign was demonstrated in 2 of 14 patients. Widespread acinar infiltrates, usually confluent, were common and were seen in 5 of 14 of our patients; in 2 of the patients, these infiltrates were due to diffuse pulmonary hemorrhage. Tracheal stenosis was the cause of sudden acute respiratory failure that was observed in one patient. Pleural disease was present in 3 of 14 patients. Hilar and mediastinal lymphadenopathy was observed in one patient. An interstitial pattern was observed in 3 of 14 patients. CONCLUSIONS We conclude that an extremely wide spectrum of radiologic findings may be observed in this disease. In 14 patients we found 11 different roentgenographic manifestations; moreover, in 8 patients it was possible to describe more than 1 radiologic manifestation at the same time or during the course of the disease. This observation is not surprising, if we consider the wide variability and broad spectrum of pathologic features in pulmonary Wegeners granulomatosis. Because conventional roentgenograms failed in a great number of cases to visualize the exact pattern and the extent of thoracic involvement, we believe that CT is particularly helpful for the assessment of pulmonary involvement in Wegeners granulomatosis.

Xerotrachea and interstitial lung disease in primary Sjogren's syndrome

22 patients with primary Sjogrens syndrome were prospectively studied for respiratory system involvement with clinical, roentgenological and functional parameters. 12 patients (55%) had respiratory manifestations. In 10/12 (83%), respiratory symptoms occurred before or concomitantly with the classical symptoms of Sjogrens syndrome. There were two distinct forms of respiratory involvement: xerotrachea, manifested by dry cough without other symptoms and negative roentgenological and functional evaluation and diffuse interstitial lung disease manifested by dyspnea with or without dry cough with bibasilar rales, compatible chest roentgenogram, restrictive pattern in spirometry and/or hypoxemia. Xerotrachea was more common in patients with glandular form of Sjogrens syndrome (3/10) and diffuse interstitial lung disease in patients with extraglandular form (6/12). None of the 22 patients had pleurisy or other forms of respiratory involvement. Antibodies to Ro (SSA) and La (SSB) antigens were more common in patients with the extraglandular form of the syndrome but did not correlate with diffuse interstitial lung disease.

Metsovo lung: Pleural calcification and restrictive lung function in northwestern Greece. Environmental exposure to mineral fiber as etiology

Pleural calcifications are described in 122 of 268 (45.5%) inhabitants of four villages (Metsovo, Anilio, Milea, and Votonosi) in a small area of northwestern Greece (total population about 5000). All affected individuals are of one ethnic group, Vlachi. Calcifications were not noted in any of the 103 persons in the control group made up of 73 non-Vlachi inhabitants from the same and neighboring villages and 30 Vlachi from distant villages. The calcifications were seen in both sexes, equally, and their frequently increased with age, from 28.6% between 30 and 39 years to 81.0% in individuals over 70 years of age. When plaque development was extensive, a small restrictive pulmonary function defect was noted. Because of its prevalence in the Metsovo area we call this clinical pattern Metsovo lung. The identification of tremolite, related amphibole fibers, and traces of chrysotile fiber in settled dusts and soil specimens and of identical fibers in tissue specimens obtained at lung biopsy from 8 people with plaques supports the hypothesis that abestiform minerals are the agents responsible for these disease processes. Further, reports of the occurrence of mesothelioma and benign pleural effusions in inhabitants in the Metsovo area, along with the striking similarities to disease patterns observed in the Karain area of Turkey, add further weight to the hypothesis that mineral fiber(s) in the environment of the four villages are agent(s) in the etiology of Metsovo lung.

Anti-Ro(SSA) positive rheumatoid arthritis (RA): a clinicoserological group of patients with high incidence of D-penicillamine side effects.

The clinical, laboratory, histological, and radiological manifestations of 90 Greek patients with anti-Ro(SSA) negative rheumatoid arthritis (RA) were compared with those of 15 Greek patients with anti-Ro(SSA) positive RA. Anti-Ro(SSA) positive RA patients had the same articular and extra-articular manifestations as anti-Ro(SSA) negative patients. However, they were predominantly females with lower rheumatoid factor titres and a high incidence of positive minor salivary gland biopsy specimens for Sjögrens syndrome. Finally, anti-Ro(SSA) positive RA patients frequently experienced penicillamine side effects.

Soluble adhesion molecules E-cadherin, intercellular adhesion molecule-1, and E-selectin as lung cancer biomarkers.

BACKGROUND Altered levels of circulating adhesion molecules found in several carcinomas, including lung cancer, reflect local loss of diffusion barriers and tumor volume and can be potentially used as biomarkers. In the present study, we investigated the role of soluble E-cadherin (sE-cad), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble E-selectin (sE-sel) as biomarkers in lung cancer. METHODS Sixty-two patients with recently diagnosed lung cancer, 42 with small cell lung cancer (SCLC), and 20 with non-small cell lung cancer (NSCLC), as well as 29 healthy volunteers were enrolled. Blood samples were collected at the time of diagnosis and measurement of soluble adhesion molecules in the serum samples was performed by enzyme-linked immunoassay using monoclonal antibodies against E-cadherin, E-selectin, and ICAM-1. RESULTS Serum levels of sE-cad, sE-sel, and sICAM-1 in both SCLC and NSCLC were significantly elevated compared with control subjects (P < .001). In addition, patients with SCLC or NSCLC with distant metastasis had a marked increase of sE-Cad (P < .001), but no such correlation with sE-sel and sICAM-1 was found. CONCLUSIONS Our findings suggest that sE-cad, sE-sel, and sICAM-1 have an adjunctive diagnostic role in lung cancer. Furthermore, sE-cad may also have a prognostic role and could be a useful biomarker in the prediction of lung cancer outcome.

High Incidence of Malignant Pleural Mesothelioma in Neighbouring Villages of Northwestern Greece

Between 1981 and 1985 seven patients from three villages of the Metsovo area in Northwestern Greece (population 5000) developed malignant pleural mesothelioma (MPM). The diagnosis was made with pleural biopsy and pleural fluid cytology. Six of these patients have died 18-24 months after the first symptoms (usually dyspnea on exertion) and 1 is still alive after 24 months. Seven MPMs in 5,000 in five years is about 280 times the expected incidence of 1/1,000,000/year. In the same area, endemic pleural calcifications linked to nonoccupational asbestos exposure have recently been reported, but none of our patients with MPM had pleural calcifications. The combination of MPM and pleural plaques in such a high frequency in the same area strongly suggests asbestos fiber as a common etiologic agent. On the other hand, the fact that the combination of MPM and pleural plaques did not occur in the same individuals, suggests a different response to this common offending agent.

Labial minor salivary gland biopsy: a highly discriminatory diagnostic method between sarcoidosis and Sjögren's syndrome.

Sixty labial minor salivary gland biopsies (lip biopsies) from 32 patients with sarcoidosis and 28 patients with primary Sjögrens syndrome were evaluated retrospectively and blindly. Six biopsies revealed typical sarcoid granulomata. All six belonged to patients with previously diagnosed sarcoidosis. Twelve lip biopsies, all from sarcoidosis patients, were classified as presenting 1+ or less lymphoid infiltrates according to Tarpleys classification. The biopsies of the remaining 14 patients with sarcoidosis showed normal tissues. Finally, 28 biopsies were classified as having 2+ or 3+ lymphoid infiltrates and/or fibrosis. All belonged to patients with Sjögrens syndrome. Our results indicate that lip biopsy has a rather low diagnostic yield in sarcoidosis (19%) but, more importantly, it can discriminate very well between sarcoidosis and Sjögrens syndrome.