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Diffuse Interstitial Pneumonitis and Fibrosis in Sarcoidosis

1988; Elsevier BV; Volume: 94; Issue: 1 Linguagem: Inglês

10.1378/chest.94.1.193

1931-3543

Seena C. Aisner, Robert J. Albin,

Medical Imaging and Pathology Studies

Interstitial pneumonitis in sarcoidosis is rare. When present, it is confined to areas of active granuloma formation. We report finding widespread interstitial pneumonitis and fibrosis in a patient with sarcoidosis. Due to the focal sampling of pulmonary tissue by transbronchial biopsy, a finding of interstitial pneumonitis does not exclude a diagnosis of sarcoidosis. Interstitial pneumonitis in sarcoidosis is rare. When present, it is confined to areas of active granuloma formation. We report finding widespread interstitial pneumonitis and fibrosis in a patient with sarcoidosis. Due to the focal sampling of pulmonary tissue by transbronchial biopsy, a finding of interstitial pneumonitis does not exclude a diagnosis of sarcoidosis. Sarcoidosis is a multisystem disorder of unknown etiology characterized pathologically by the formation of non-necrotizing granulomata in multiple sites in the body. Although the clinical and radiographic presentation of cases is quite characteristic, a histologic diagnosis is necessary before beginning treatment. Fiberoptic bronchoscopy with transbronchial lung biopsies is diagnostic in 60 to 95 percent of cases, depending upon the clinical stage of the disease.1Roethe RA Fuller PB Byrd RB Hafermann DR Transbronchoscopic lung biopsy in sarcoidosis: optimal number and sites for diagnosis.Chest. 1980; 77: 400-402Crossref PubMed Scopus (82) Google Scholar, 2Koontz CH Joyner LR Nelson RA Transbronchial lung biopsy via the fiberoptic bronchoscope in sarcoidosis.Ann Intern Med. 1976; 85: 64-66Crossref PubMed Scopus (103) Google Scholar The diagnosis is established when non-necrotizing epithelioid granulomata with giant cells are found on biopsy and cultures are negative. While interstitial fibrosis and interstitial pneumonitis have been reported in sarcoidosis, they are usually localized to areas of extensive involvement with active granulomatous disease.3Mitchell DN Scadding JD Heard BE Hinson KFW Sarcoidosis: histopathological definition and clinical diagnosis.J Clin Pathol. 1977; 30: 395-408Crossref PubMed Scopus (160) Google Scholar We report a case of pulmonary sarcoidosis with extensive interstitial pneumonitis and fibrosis in regions without active granuloma formation.Case ReportA previously healthy 27-year-old black woman presented to the emergency room at the University of Maryland Medical Systems complaining of dyspnea and a nonproductive cough for the past 12 months. Her exercise capacity had diminished to the point of severe dyspnea after walking one block. She recently noted arthralgias, and there was a 5.4-kg (12-lb) weight loss. There was a 14 pack-year history of smoking, but the patient had discontinued smoking cigarettes three months prior to admission. She had previously smoked marijuana for many years and recently began snorting cocaine. There was no occupational history of exposure to toxins.Physical examination was remarkable only for the presence of fine end-inspiratory crackles on auscultation and digital clubbing. Admitting laboratory studies revealed a hematocrit reading of 47 percent and a white blood cell count of 6,100/cu mm, with a normal differential. The serum calcium level was 9.6 mg/dl, and the alkaline phosphatase level was 366 units (normal, 95 to 300 units). An arterial blood specimen while breathing room air revealed a pH of 7.39, an arterial carbon dioxide tension of 35 mm Hg, and an arterial oxygen pressure of 72 mm Hg. The chest roentgenogram demonstrated bilateral paratracheal and perihilar lymphadenopathy with a diffuse, reticulonodular parenchymal infiltrate (Fig 1). There was no pleural thickening or effusion. The patient was unable to perform pulmonary function tests due to dyspnea and cough.The patient underwent flexible fiberoptic bronchoscopic examination, which showed a cobblestone pattern in the airways but no endobronchial lesions. Microscopic examination of the transbronchial biopsies revealed diffuse interstitial fibrosis and inflammation (Fig 2). No granulomata or giant cells were seen. Pulmonary macrophages and mononuclear cells were found within the alveolar air spaces. These findings were suggestive of a diagnosis of desquamative interstitial pneumonitis; however, because this diagnosis failed to explain the intrathoracic adenopathy, the patient underwent mediastinal lymph node and open lung biopsies.Figure 2Transbronchial lung biopsy showing interstital thickening with chronic inflammatory cells. Note alveolar cell hyperplasia (thick arrow) and mononuclear cells in alveolar spaces (thin arrow) (hematoxylin-eosin, original magnification ×900).View Large Image Figure ViewerDownload (PPT)Histologic examination of the mediastinal lymph node revealed complete effacement of the normal nodal architecture by non-necrotizing epithelioid granulomata. The wedge biopsy from the lingula revealed no areas of normal lung. The parenchyma showed extensive interstitial pneumonitis and fibrosis, with reactive alveolar cell hyperplasia in areas not associated with active granuloma formation (Fig 3). There were focal aggregates of acid-fast bacillus-negative non-necrotizing granulomata within the alveolar septa. Peripheral honeycombing with formation of bullae was evident in the subpleura.Figure 3Open wedge biopsy from peripheral lung. Note marked interstital fibrosis and alveolar cell hyperplasia. Granulomata are not seen in this field (hematoxylin-eosin, original magnification ×570).View Large Image Figure ViewerDownload (PPT)The patient was discharged on a regimen of 40 mg of prednisone. On follow-up, she was no longer coughing, her exercise tolerance had improved, and she was gaining weight.DiscussionExtensive interstitial pneumonitis was the predominant pathologic finding in this patient with sarcoidosis. Although granulomata were present in the alveolar septa, their sparseness in the pulmonary parenchyma fails to explain the marked degree of interstitial inflammation present. While interstitial pneumonitis has been associated with diseases in which there are altered immune mechanisms, there was no clinical or serologic evidence for an immunologic disorder in this patient.4Spencer H Pathology of the lung. Pergamon Press, New York1985: 824-832Google ScholarInterstitial pneumonitis in sarcoidosis is infrequently recognized. Katzenstein and Aslan5Katzenstein AA Askin FB Surgical pathology of non-neoplastic lung disease. WB Saunders Co, Philadelphia1982: 152-158Google Scholar state that there is little, if any, interstitial pneumonitis surrounding the granulomata in the lung. Spencer4Spencer H Pathology of the lung. Pergamon Press, New York1985: 824-832Google Scholar makes no mention of interstitial pneumonitis in his discussion of the histopathologic findings in sarcoidosis. In contrast, Rosen and co-workers6Rosen Y Athanassiades TJ Moon S Lyons HA Nongranulomatous interstitial pneumonitis in sarcoidosis: relationship to development of epithelioid granulomas.Chest. 1978; 74: 122-125Crossref PubMed Scopus (97) Google Scholar reported finding focal, nonspecific interstitial pneumonitis in 62 percent of 128 open lung biopsies performed for presumed sarcoidosis. All biopsies from their series demonstrated granulomata. Based upon their observation that several regions of pneumonitis were organizing into granulomata, Rosen et al6Rosen Y Athanassiades TJ Moon S Lyons HA Nongranulomatous interstitial pneumonitis in sarcoidosis: relationship to development of epithelioid granulomas.Chest. 1978; 74: 122-125Crossref PubMed Scopus (97) Google Scholar suggested that interstitial pneumonitis represented the earliest phase of granuloma development. Our patient differed from their cases in two respects. First, the interstitial pneumonitis was diffuse, and, secondly, the patient had evidence of advanced sarcoidosis, with parenchymal honeycombing and fibrosis.It appears that the interstitial pneumonitis and secondary fibrosis in our case occurred independent from active granuloma formation. This raises the question of whether a second disease or drug exposure could account for these changes. Although the transbronchial lung biopsies suggested desquamative interstitial pneumonitis, the open lung biopsy ruled this out. The major histopathologic findings in marijuana smokers from a recent postmortem series were alveolar infiltration with pigmented macrophages and varying degrees of monocytic and lymphocytic infiltration in the pulmonary interstitium.7Morris RR Human pulmonary histopathological changes from marijuana smoking.J Forensic Sci. 1985; 30: 345-349Crossref PubMed Google Scholar These findings were not present in this case. Similarly, a postmortem series involving cocaine abusers failed to demonstrate interstitial pneumonitis.8Mittleman RE Wetli CV Death caused by recreational cocaine use: an update.JAMA. 1984; 252: 1889-1893Crossref PubMed Scopus (197) Google Scholar Our patient abused no other drugs, had no evidence of a collagen-vascular disorder, and was not exposed to any toxic substances at her place of employment.While a second disease cannot be completely excluded, we believe that this case represents an unusual histopathologic presentation of sarcoidosis and demonstrates several important points. First, diffuse interstitial pneumonitis may be seen in advanced sarcoidosis. Secondly, interstitial pneumonitis and alveolar cell hyperplasia without closely associated granulomata or giant cells can be found in sarcoidosis. This may be especially important when evaluating small pieces of tissue from transbronchial lung biopsies. In this context, transbronchial lung biopsies which reveal these findings alone do not exclude the diagnosis of pulmonary sarcoidosis. Additional biopsy material should be obtained when sarcoidosis is suspected and the histologic findings reveal only interstitial pneumonitis or fibrosis.ACKNOWLEDGMENTWe thank Mr. Perry Comegys for his technical assistance in the preparation of the photomicrographs. Sarcoidosis is a multisystem disorder of unknown etiology characterized pathologically by the formation of non-necrotizing granulomata in multiple sites in the body. Although the clinical and radiographic presentation of cases is quite characteristic, a histologic diagnosis is necessary before beginning treatment. Fiberoptic bronchoscopy with transbronchial lung biopsies is diagnostic in 60 to 95 percent of cases, depending upon the clinical stage of the disease.1Roethe RA Fuller PB Byrd RB Hafermann DR Transbronchoscopic lung biopsy in sarcoidosis: optimal number and sites for diagnosis.Chest. 1980; 77: 400-402Crossref PubMed Scopus (82) Google Scholar, 2Koontz CH Joyner LR Nelson RA Transbronchial lung biopsy via the fiberoptic bronchoscope in sarcoidosis.Ann Intern Med. 1976; 85: 64-66Crossref PubMed Scopus (103) Google Scholar The diagnosis is established when non-necrotizing epithelioid granulomata with giant cells are found on biopsy and cultures are negative. While interstitial fibrosis and interstitial pneumonitis have been reported in sarcoidosis, they are usually localized to areas of extensive involvement with active granulomatous disease.3Mitchell DN Scadding JD Heard BE Hinson KFW Sarcoidosis: histopathological definition and clinical diagnosis.J Clin Pathol. 1977; 30: 395-408Crossref PubMed Scopus (160) Google Scholar We report a case of pulmonary sarcoidosis with extensive interstitial pneumonitis and fibrosis in regions without active granuloma formation. Case ReportA previously healthy 27-year-old black woman presented to the emergency room at the University of Maryland Medical Systems complaining of dyspnea and a nonproductive cough for the past 12 months. Her exercise capacity had diminished to the point of severe dyspnea after walking one block. She recently noted arthralgias, and there was a 5.4-kg (12-lb) weight loss. There was a 14 pack-year history of smoking, but the patient had discontinued smoking cigarettes three months prior to admission. She had previously smoked marijuana for many years and recently began snorting cocaine. There was no occupational history of exposure to toxins.Physical examination was remarkable only for the presence of fine end-inspiratory crackles on auscultation and digital clubbing. Admitting laboratory studies revealed a hematocrit reading of 47 percent and a white blood cell count of 6,100/cu mm, with a normal differential. The serum calcium level was 9.6 mg/dl, and the alkaline phosphatase level was 366 units (normal, 95 to 300 units). An arterial blood specimen while breathing room air revealed a pH of 7.39, an arterial carbon dioxide tension of 35 mm Hg, and an arterial oxygen pressure of 72 mm Hg. The chest roentgenogram demonstrated bilateral paratracheal and perihilar lymphadenopathy with a diffuse, reticulonodular parenchymal infiltrate (Fig 1). There was no pleural thickening or effusion. The patient was unable to perform pulmonary function tests due to dyspnea and cough.The patient underwent flexible fiberoptic bronchoscopic examination, which showed a cobblestone pattern in the airways but no endobronchial lesions. Microscopic examination of the transbronchial biopsies revealed diffuse interstitial fibrosis and inflammation (Fig 2). No granulomata or giant cells were seen. Pulmonary macrophages and mononuclear cells were found within the alveolar air spaces. These findings were suggestive of a diagnosis of desquamative interstitial pneumonitis; however, because this diagnosis failed to explain the intrathoracic adenopathy, the patient underwent mediastinal lymph node and open lung biopsies.Histologic examination of the mediastinal lymph node revealed complete effacement of the normal nodal architecture by non-necrotizing epithelioid granulomata. The wedge biopsy from the lingula revealed no areas of normal lung. The parenchyma showed extensive interstitial pneumonitis and fibrosis, with reactive alveolar cell hyperplasia in areas not associated with active granuloma formation (Fig 3). There were focal aggregates of acid-fast bacillus-negative non-necrotizing granulomata within the alveolar septa. Peripheral honeycombing with formation of bullae was evident in the subpleura.Figure 3Open wedge biopsy from peripheral lung. Note marked interstital fibrosis and alveolar cell hyperplasia. Granulomata are not seen in this field (hematoxylin-eosin, original magnification ×570).View Large Image Figure ViewerDownload (PPT)The patient was discharged on a regimen of 40 mg of prednisone. On follow-up, she was no longer coughing, her exercise tolerance had improved, and she was gaining weight. A previously healthy 27-year-old black woman presented to the emergency room at the University of Maryland Medical Systems complaining of dyspnea and a nonproductive cough for the past 12 months. Her exercise capacity had diminished to the point of severe dyspnea after walking one block. She recently noted arthralgias, and there was a 5.4-kg (12-lb) weight loss. There was a 14 pack-year history of smoking, but the patient had discontinued smoking cigarettes three months prior to admission. She had previously smoked marijuana for many years and recently began snorting cocaine. There was no occupational history of exposure to toxins. Physical examination was remarkable only for the presence of fine end-inspiratory crackles on auscultation and digital clubbing. Admitting laboratory studies revealed a hematocrit reading of 47 percent and a white blood cell count of 6,100/cu mm, with a normal differential. The serum calcium level was 9.6 mg/dl, and the alkaline phosphatase level was 366 units (normal, 95 to 300 units). An arterial blood specimen while breathing room air revealed a pH of 7.39, an arterial carbon dioxide tension of 35 mm Hg, and an arterial oxygen pressure of 72 mm Hg. The chest roentgenogram demonstrated bilateral paratracheal and perihilar lymphadenopathy with a diffuse, reticulonodular parenchymal infiltrate (Fig 1). There was no pleural thickening or effusion. The patient was unable to perform pulmonary function tests due to dyspnea and cough. The patient underwent flexible fiberoptic bronchoscopic examination, which showed a cobblestone pattern in the airways but no endobronchial lesions. Microscopic examination of the transbronchial biopsies revealed diffuse interstitial fibrosis and inflammation (Fig 2). No granulomata or giant cells were seen. Pulmonary macrophages and mononuclear cells were found within the alveolar air spaces. These findings were suggestive of a diagnosis of desquamative interstitial pneumonitis; however, because this diagnosis failed to explain the intrathoracic adenopathy, the patient underwent mediastinal lymph node and open lung biopsies. Histologic examination of the mediastinal lymph node revealed complete effacement of the normal nodal architecture by non-necrotizing epithelioid granulomata. The wedge biopsy from the lingula revealed no areas of normal lung. The parenchyma showed extensive interstitial pneumonitis and fibrosis, with reactive alveolar cell hyperplasia in areas not associated with active granuloma formation (Fig 3). There were focal aggregates of acid-fast bacillus-negative non-necrotizing granulomata within the alveolar septa. Peripheral honeycombing with formation of bullae was evident in the subpleura. The patient was discharged on a regimen of 40 mg of prednisone. On follow-up, she was no longer coughing, her exercise tolerance had improved, and she was gaining weight. DiscussionExtensive interstitial pneumonitis was the predominant pathologic finding in this patient with sarcoidosis. Although granulomata were present in the alveolar septa, their sparseness in the pulmonary parenchyma fails to explain the marked degree of interstitial inflammation present. While interstitial pneumonitis has been associated with diseases in which there are altered immune mechanisms, there was no clinical or serologic evidence for an immunologic disorder in this patient.4Spencer H Pathology of the lung. Pergamon Press, New York1985: 824-832Google ScholarInterstitial pneumonitis in sarcoidosis is infrequently recognized. Katzenstein and Aslan5Katzenstein AA Askin FB Surgical pathology of non-neoplastic lung disease. WB Saunders Co, Philadelphia1982: 152-158Google Scholar state that there is little, if any, interstitial pneumonitis surrounding the granulomata in the lung. Spencer4Spencer H Pathology of the lung. Pergamon Press, New York1985: 824-832Google Scholar makes no mention of interstitial pneumonitis in his discussion of the histopathologic findings in sarcoidosis. In contrast, Rosen and co-workers6Rosen Y Athanassiades TJ Moon S Lyons HA Nongranulomatous interstitial pneumonitis in sarcoidosis: relationship to development of epithelioid granulomas.Chest. 1978; 74: 122-125Crossref PubMed Scopus (97) Google Scholar reported finding focal, nonspecific interstitial pneumonitis in 62 percent of 128 open lung biopsies performed for presumed sarcoidosis. All biopsies from their series demonstrated granulomata. Based upon their observation that several regions of pneumonitis were organizing into granulomata, Rosen et al6Rosen Y Athanassiades TJ Moon S Lyons HA Nongranulomatous interstitial pneumonitis in sarcoidosis: relationship to development of epithelioid granulomas.Chest. 1978; 74: 122-125Crossref PubMed Scopus (97) Google Scholar suggested that interstitial pneumonitis represented the earliest phase of granuloma development. Our patient differed from their cases in two respects. First, the interstitial pneumonitis was diffuse, and, secondly, the patient had evidence of advanced sarcoidosis, with parenchymal honeycombing and fibrosis.It appears that the interstitial pneumonitis and secondary fibrosis in our case occurred independent from active granuloma formation. This raises the question of whether a second disease or drug exposure could account for these changes. Although the transbronchial lung biopsies suggested desquamative interstitial pneumonitis, the open lung biopsy ruled this out. The major histopathologic findings in marijuana smokers from a recent postmortem series were alveolar infiltration with pigmented macrophages and varying degrees of monocytic and lymphocytic infiltration in the pulmonary interstitium.7Morris RR Human pulmonary histopathological changes from marijuana smoking.J Forensic Sci. 1985; 30: 345-349Crossref PubMed Google Scholar These findings were not present in this case. Similarly, a postmortem series involving cocaine abusers failed to demonstrate interstitial pneumonitis.8Mittleman RE Wetli CV Death caused by recreational cocaine use: an update.JAMA. 1984; 252: 1889-1893Crossref PubMed Scopus (197) Google Scholar Our patient abused no other drugs, had no evidence of a collagen-vascular disorder, and was not exposed to any toxic substances at her place of employment.While a second disease cannot be completely excluded, we believe that this case represents an unusual histopathologic presentation of sarcoidosis and demonstrates several important points. First, diffuse interstitial pneumonitis may be seen in advanced sarcoidosis. Secondly, interstitial pneumonitis and alveolar cell hyperplasia without closely associated granulomata or giant cells can be found in sarcoidosis. This may be especially important when evaluating small pieces of tissue from transbronchial lung biopsies. In this context, transbronchial lung biopsies which reveal these findings alone do not exclude the diagnosis of pulmonary sarcoidosis. Additional biopsy material should be obtained when sarcoidosis is suspected and the histologic findings reveal only interstitial pneumonitis or fibrosis. Extensive interstitial pneumonitis was the predominant pathologic finding in this patient with sarcoidosis. Although granulomata were present in the alveolar septa, their sparseness in the pulmonary parenchyma fails to explain the marked degree of interstitial inflammation present. While interstitial pneumonitis has been associated with diseases in which there are altered immune mechanisms, there was no clinical or serologic evidence for an immunologic disorder in this patient.4Spencer H Pathology of the lung. Pergamon Press, New York1985: 824-832Google Scholar Interstitial pneumonitis in sarcoidosis is infrequently recognized. Katzenstein and Aslan5Katzenstein AA Askin FB Surgical pathology of non-neoplastic lung disease. WB Saunders Co, Philadelphia1982: 152-158Google Scholar state that there is little, if any, interstitial pneumonitis surrounding the granulomata in the lung. Spencer4Spencer H Pathology of the lung. Pergamon Press, New York1985: 824-832Google Scholar makes no mention of interstitial pneumonitis in his discussion of the histopathologic findings in sarcoidosis. In contrast, Rosen and co-workers6Rosen Y Athanassiades TJ Moon S Lyons HA Nongranulomatous interstitial pneumonitis in sarcoidosis: relationship to development of epithelioid granulomas.Chest. 1978; 74: 122-125Crossref PubMed Scopus (97) Google Scholar reported finding focal, nonspecific interstitial pneumonitis in 62 percent of 128 open lung biopsies performed for presumed sarcoidosis. All biopsies from their series demonstrated granulomata. Based upon their observation that several regions of pneumonitis were organizing into granulomata, Rosen et al6Rosen Y Athanassiades TJ Moon S Lyons HA Nongranulomatous interstitial pneumonitis in sarcoidosis: relationship to development of epithelioid granulomas.Chest. 1978; 74: 122-125Crossref PubMed Scopus (97) Google Scholar suggested that interstitial pneumonitis represented the earliest phase of granuloma development. Our patient differed from their cases in two respects. First, the interstitial pneumonitis was diffuse, and, secondly, the patient had evidence of advanced sarcoidosis, with parenchymal honeycombing and fibrosis. It appears that the interstitial pneumonitis and secondary fibrosis in our case occurred independent from active granuloma formation. This raises the question of whether a second disease or drug exposure could account for these changes. Although the transbronchial lung biopsies suggested desquamative interstitial pneumonitis, the open lung biopsy ruled this out. The major histopathologic findings in marijuana smokers from a recent postmortem series were alveolar infiltration with pigmented macrophages and varying degrees of monocytic and lymphocytic infiltration in the pulmonary interstitium.7Morris RR Human pulmonary histopathological changes from marijuana smoking.J Forensic Sci. 1985; 30: 345-349Crossref PubMed Google Scholar These findings were not present in this case. Similarly, a postmortem series involving cocaine abusers failed to demonstrate interstitial pneumonitis.8Mittleman RE Wetli CV Death caused by recreational cocaine use: an update.JAMA. 1984; 252: 1889-1893Crossref PubMed Scopus (197) Google Scholar Our patient abused no other drugs, had no evidence of a collagen-vascular disorder, and was not exposed to any toxic substances at her place of employment. While a second disease cannot be completely excluded, we believe that this case represents an unusual histopathologic presentation of sarcoidosis and demonstrates several important points. First, diffuse interstitial pneumonitis may be seen in advanced sarcoidosis. Secondly, interstitial pneumonitis and alveolar cell hyperplasia without closely associated granulomata or giant cells can be found in sarcoidosis. This may be especially important when evaluating small pieces of tissue from transbronchial lung biopsies. In this context, transbronchial lung biopsies which reveal these findings alone do not exclude the diagnosis of pulmonary sarcoidosis. Additional biopsy material should be obtained when sarcoidosis is suspected and the histologic findings reveal only interstitial pneumonitis or fibrosis. ACKNOWLEDGMENTWe thank Mr. Perry Comegys for his technical assistance in the preparation of the photomicrographs. We thank Mr. Perry Comegys for his technical assistance in the preparation of the photomicrographs.