Case Reports Pulmonary Histiocytosis X with Mediastinal Lymph Node Involvement1.2
ELISABETH BRAMBILLA, ERIC FONTAINE, CHRISTOPHE M. PISON, MAX COULOMB, BERNARD PARAMELLE, and CHRISTIAN BRAMBILLA
Introduction Histiocytosis X is a granulomatous disorder of unknown cause involving various sites. Depending on the site, the clinical presentation may be either localized or disseminated. Pulmonary histiocytosisX was first described in 1951 (1) and has been found concurrently in other sites, including bones (8OJo) and/or hypothalami (7%) (2). Although mediastinal lymph node enlargement has been reported (3, 4), it has never, to our knowledge, been histologically documented. We report such a case here. Case Report A 33-yr-old Caucasian arc welder who smoked presented with general ill health. He was examined radiologically and found to have an abnormal roentgenogram: He had a history of pulmonary tuberculosis that he had contracted at 3 yr of age. This arc welder had complained for three months of a nonproductive cough, weakness, anorexia, night sweats, an 8-kg weight loss, and hyperthermia (38.5 0 C) . Clinical examination showed a painless, left submandibular, lymph adenopathy. A chest roentgenogram showed interstitial, micronodular, and reticular densities throughout both lungs. These
SUMMARY In this report. we describe a patient with the classic histology of pUlmonary histiocytosis X, who had bilateral retlculonodular densities and mediastinal lymph node involvement. The diagnosis was confirmed by the use of electron microscopy and Immunohistochemical markers (PS100, HLA-OR, and COl). which allowed us to recognize the lymph node Infiltration of X hlstlocytes. An association of mediastinal lymph node enlargement with pUlmonary histiocytosis X has been reported but it has never been histologically documented. AM REV RESPIR DIS 1990; 142:1216-1218
changes were prominent in the middle zones of the lung. Mediastinal lymph node enlargement was observed, with shadowing in the aorticopulmonary window (figure I). The erythrocyte sedimentation rate was elevated (46 mm during the first hour). White blood cell count was 14,700/ml: 73010 polymorphonuclear leukocytes, 15010 lymphocytes, and 7010 eosinophils. There wereno autoantibodies, and HIV serology was negative.Blood cultures were sterile. A search for mycobacteria and Legionella in the sputum gave negative results. Blood gas levels were normal at rest (pao" 87 mm Hg; Paco" 40 mm Hg ; Sao" 96010 ; pH 7.35); however. a slight desaturation occurred after exercise (after 10 min at 100 watts: Pao, 81 mm Hg; Paeo" 35 mm Hg; Sao" 94010; pH 7.30). Lung function tests showed pulmonary restriction (TLC, 56010 of the predicted value) without
showing any obstructive syndrome (FEV, /VC, 105010 of the predicted value). Carbon monoxide diffusion was slightly decreased (DLeo/VA, 71010 of the predicted value) .
(Received in original form December 7, 1989 and in revised form May 15, 1990) 1 From the Division of Lung Disease and the Departments of Pathology and Radiology, Hopital A. Michallon, Joseph Fourier University, Greno ble, France. , Correspondence and requests for reprints should be addressed to E . Brambilla, Service d'Anatomo-Pathologie, Hopital A. Michallon, BP 217 X, 38043 Grenoble Cedex, France.
Fig. 1 (left). Chest roentgenogram showing bilateral interstitial densities and shadowing in the aorticopulmonary window. Fig. 2 (right). Histologic aspect of pulmonary histiocytosis X infiltrates : large X histiocytes are enlarging alveolar walls (x250).
1216
CASE REPORT
1217 in the cytopla sm of the histiocytic cells (figu re 4). Today, the patient suffers from progressive declining respiratory function with hypoxia at rest and severe disabilit y, desp ite cytoto xic chemotherap y. This progressive pulmonary in sufficiency may ultimately lead to lung transplantation.
Fig. 3. Nodular aggregate of X histiocytes in mediastinal lymph node (top) (x250); positive staining ofthese histiocytes with PS 100 (bottom) (x250) .
Bronchoscopy was normal. The cytologic smears and the bacteriologi c and parasitologic cultures were negative . A computed tomography scan showed bilateral nodules and micro cysts throughout both lun g fields and in the right paratracheal and anteromediastinal lymph nodes , whose size did no t exceed 10 mm in diame ter. Med iastinoscopy with rapid frozen section examination gave negative results. A lung biopsy was performed. Under gross examination, mediastinal samples were beige. Rapid frozen section examination permitted only the recognition of sinal hyperplasia. Lung samples exh ibited mult iple gra yish nodules I to 3 mm in diameter, some of which had a minute cavity in the center. On examination by microscopy, these nodules were histiocytic granulomata that had infiltrated the alveolar walls along their border (figure 2). The granulomata were com-
posed mainly of large histiocytic cells with abundant eosinophilic cytoplasm and a pale, multifolded nucleus with inconspicuous nucleoli. Small numbers of lymphocytes, polymorphonuclear leukocytes, and eosinophils were scattered throughout the periphery of the in filtrates. This histologic pattern is, therefore, typical of pulmonary histio cytosis X. Paraffin section examination of mediastinallymph nodes showed reactive hyperplasia and focal nodular infiltration of the perifollicular spaces and sinuses by the same histiocytes (figure 3). Immunochem istry was performed using an indirect immunoperoxidase technique. Histiocytes stained positive for COl (OKT6), HLA-DR, and SIOO protein (PSlOO) antibodies and negative for CD4 (OKT4) (figure 3). Thi s phenotype is characteristic of Langerhans cells. Electron microscopic study of the lung samples showed numerous X bodies
Discussion The association of mediastinal lymph node enlargement with pulmonary histiocytosis X has been reported previously (3 ,4). Although enlargement ofhilar lymph nodes was not observed in a series of 50 cases (5, 6), Friedman and colleagues (4) reported definite adenopathy in 3070 of the patients and possible adenopathy in 20% of the patients in a series of 100 cases. However, when histologic examination was done, only a nonspecific follicular hyperplasia was noted. In contrast, lymph node involvement in systemic histiocytosis X is well known. Mottoi and coworker s (7) reported 30 cases of eosinophilic granuloma exclusively restricted to lymph nodes ; in this series, there were only .two cases of mediastinal lymph node enlargement. Williams and Dorfman (8) reported 17 cases of histiocytosis X where lymph node involvement was found with other locations. Tho of these cases showed bilateral interstitial infiltrates, without mediastinal enlargement. The present case report is, to our knowledge, the first case of pulmonary histiocytosis X where mediastinal lymph node involvement has been histologically and immunohistochemically proven. The histologic features of the lymph nodes are the same as those described previously (7). The phenotype of the X histiocyte markers is that of the Langerhans cells: COl, HLA-DR, and PS100. These markers, which are diagnostic of Langerhans cell histiocytosis (9), are also shared by the interdigitating reticulum cells of normal lymph nodes. In the present case, however, neither the nodular aggregates nor the cytologic features of the positive cells werethose of normal interdigitating reticulum cells. Examination by electron microscopy confirmed this diagnosis by showing the existence of numerous Birbeck or X bodies in this histiocytic population. Because lung transplantation had been proposed as further treatment in this young patient, the presence of mediastinal involvement of histiocytos is X suggests that heart-lung transplantation would be preferable to bilateral lung transplantation.
Acknowledgment The writer s are indebted to Dr. D. Veale and Mr s. Willison for reviewing the manuscript.
References 1. Far inacci CJ, Jeffrey H C, Lackey RW. Eo-
sinophilic granuloma of the lung. U.S. Armed Forces Med J 1951; 2:1085-93. 2. Marcy TW, Reynolds HY. Pulmonary histiocytosis X. Lung 1985; 163:129-50. 3. Masson RG, Tedeschi LG. Pulmonary eosinophilic granuloma with hilar adenopathy simulating sarco idosis . Ch est 1978; 73:682-3 .
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CASE REPORT
4. Friedman PJ, Liebow AA, Sokoloff J. Eosinophilic granuloma of lung. Medicine 1981; 60:385-96.
5. Basset F, Corrin B, Spencer H, et al. Pulmonary histiocytosis X. Am Rev Respir Dis 1978; 118:811-20.
6. Lacronique J, Roth C, Battesti JP, Chretien J . Chest radiological features of pulmonary histiocytosis X. Thorax 1982; 37:104-9. 7. Mottoi M, Helbron D, Kaiserling E, Lennert K. Eosinophilic granuloma of lymph nodes: a variant of histiocytosis X. Histopathology 1980; 4:585-606.
8. Williams JW, Dorfman RF. Lymphadenopathy as the initial manifestation of histiocytosis X. Am J Surg Pathol 1979; 3:405-21. 9. Writing Group of the Histiocyte Society. Histiocytosis syndrome in children. Lancet 1987; 1:208-9.
Fig . 4. Electron micrographs illust rating histiocytes X in the lung (top) (x12,BOO). High magnification of X bodies (bottom) (x56,OOO).
ELISABETH BRAMBILLA, ERIC FONTAINE, CHRISTOPHE M. PISON, MAX COULOMB, BERNARD PARAMELLE, and CHRISTIAN BRAMBILLA
Introduction Histiocytosis X is a granulomatous disorder of unknown cause involving various sites. Depending on the site, the clinical presentation may be either localized or disseminated. Pulmonary histiocytosisX was first described in 1951 (1) and has been found concurrently in other sites, including bones (8OJo) and/or hypothalami (7%) (2). Although mediastinal lymph node enlargement has been reported (3, 4), it has never, to our knowledge, been histologically documented. We report such a case here. Case Report A 33-yr-old Caucasian arc welder who smoked presented with general ill health. He was examined radiologically and found to have an abnormal roentgenogram: He had a history of pulmonary tuberculosis that he had contracted at 3 yr of age. This arc welder had complained for three months of a nonproductive cough, weakness, anorexia, night sweats, an 8-kg weight loss, and hyperthermia (38.5 0 C) . Clinical examination showed a painless, left submandibular, lymph adenopathy. A chest roentgenogram showed interstitial, micronodular, and reticular densities throughout both lungs. These
SUMMARY In this report. we describe a patient with the classic histology of pUlmonary histiocytosis X, who had bilateral retlculonodular densities and mediastinal lymph node involvement. The diagnosis was confirmed by the use of electron microscopy and Immunohistochemical markers (PS100, HLA-OR, and COl). which allowed us to recognize the lymph node Infiltration of X hlstlocytes. An association of mediastinal lymph node enlargement with pUlmonary histiocytosis X has been reported but it has never been histologically documented. AM REV RESPIR DIS 1990; 142:1216-1218
changes were prominent in the middle zones of the lung. Mediastinal lymph node enlargement was observed, with shadowing in the aorticopulmonary window (figure I). The erythrocyte sedimentation rate was elevated (46 mm during the first hour). White blood cell count was 14,700/ml: 73010 polymorphonuclear leukocytes, 15010 lymphocytes, and 7010 eosinophils. There wereno autoantibodies, and HIV serology was negative.Blood cultures were sterile. A search for mycobacteria and Legionella in the sputum gave negative results. Blood gas levels were normal at rest (pao" 87 mm Hg; Paco" 40 mm Hg ; Sao" 96010 ; pH 7.35); however. a slight desaturation occurred after exercise (after 10 min at 100 watts: Pao, 81 mm Hg; Paeo" 35 mm Hg; Sao" 94010; pH 7.30). Lung function tests showed pulmonary restriction (TLC, 56010 of the predicted value) without
showing any obstructive syndrome (FEV, /VC, 105010 of the predicted value). Carbon monoxide diffusion was slightly decreased (DLeo/VA, 71010 of the predicted value) .
(Received in original form December 7, 1989 and in revised form May 15, 1990) 1 From the Division of Lung Disease and the Departments of Pathology and Radiology, Hopital A. Michallon, Joseph Fourier University, Greno ble, France. , Correspondence and requests for reprints should be addressed to E . Brambilla, Service d'Anatomo-Pathologie, Hopital A. Michallon, BP 217 X, 38043 Grenoble Cedex, France.
Fig. 1 (left). Chest roentgenogram showing bilateral interstitial densities and shadowing in the aorticopulmonary window. Fig. 2 (right). Histologic aspect of pulmonary histiocytosis X infiltrates : large X histiocytes are enlarging alveolar walls (x250).
1216
CASE REPORT
1217 in the cytopla sm of the histiocytic cells (figu re 4). Today, the patient suffers from progressive declining respiratory function with hypoxia at rest and severe disabilit y, desp ite cytoto xic chemotherap y. This progressive pulmonary in sufficiency may ultimately lead to lung transplantation.
Fig. 3. Nodular aggregate of X histiocytes in mediastinal lymph node (top) (x250); positive staining ofthese histiocytes with PS 100 (bottom) (x250) .
Bronchoscopy was normal. The cytologic smears and the bacteriologi c and parasitologic cultures were negative . A computed tomography scan showed bilateral nodules and micro cysts throughout both lun g fields and in the right paratracheal and anteromediastinal lymph nodes , whose size did no t exceed 10 mm in diame ter. Med iastinoscopy with rapid frozen section examination gave negative results. A lung biopsy was performed. Under gross examination, mediastinal samples were beige. Rapid frozen section examination permitted only the recognition of sinal hyperplasia. Lung samples exh ibited mult iple gra yish nodules I to 3 mm in diameter, some of which had a minute cavity in the center. On examination by microscopy, these nodules were histiocytic granulomata that had infiltrated the alveolar walls along their border (figure 2). The granulomata were com-
posed mainly of large histiocytic cells with abundant eosinophilic cytoplasm and a pale, multifolded nucleus with inconspicuous nucleoli. Small numbers of lymphocytes, polymorphonuclear leukocytes, and eosinophils were scattered throughout the periphery of the in filtrates. This histologic pattern is, therefore, typical of pulmonary histio cytosis X. Paraffin section examination of mediastinallymph nodes showed reactive hyperplasia and focal nodular infiltration of the perifollicular spaces and sinuses by the same histiocytes (figure 3). Immunochem istry was performed using an indirect immunoperoxidase technique. Histiocytes stained positive for COl (OKT6), HLA-DR, and SIOO protein (PSlOO) antibodies and negative for CD4 (OKT4) (figure 3). Thi s phenotype is characteristic of Langerhans cells. Electron microscopic study of the lung samples showed numerous X bodies
Discussion The association of mediastinal lymph node enlargement with pulmonary histiocytosis X has been reported previously (3 ,4). Although enlargement ofhilar lymph nodes was not observed in a series of 50 cases (5, 6), Friedman and colleagues (4) reported definite adenopathy in 3070 of the patients and possible adenopathy in 20% of the patients in a series of 100 cases. However, when histologic examination was done, only a nonspecific follicular hyperplasia was noted. In contrast, lymph node involvement in systemic histiocytosis X is well known. Mottoi and coworker s (7) reported 30 cases of eosinophilic granuloma exclusively restricted to lymph nodes ; in this series, there were only .two cases of mediastinal lymph node enlargement. Williams and Dorfman (8) reported 17 cases of histiocytosis X where lymph node involvement was found with other locations. Tho of these cases showed bilateral interstitial infiltrates, without mediastinal enlargement. The present case report is, to our knowledge, the first case of pulmonary histiocytosis X where mediastinal lymph node involvement has been histologically and immunohistochemically proven. The histologic features of the lymph nodes are the same as those described previously (7). The phenotype of the X histiocyte markers is that of the Langerhans cells: COl, HLA-DR, and PS100. These markers, which are diagnostic of Langerhans cell histiocytosis (9), are also shared by the interdigitating reticulum cells of normal lymph nodes. In the present case, however, neither the nodular aggregates nor the cytologic features of the positive cells werethose of normal interdigitating reticulum cells. Examination by electron microscopy confirmed this diagnosis by showing the existence of numerous Birbeck or X bodies in this histiocytic population. Because lung transplantation had been proposed as further treatment in this young patient, the presence of mediastinal involvement of histiocytos is X suggests that heart-lung transplantation would be preferable to bilateral lung transplantation.
Acknowledgment The writer s are indebted to Dr. D. Veale and Mr s. Willison for reviewing the manuscript.
References 1. Far inacci CJ, Jeffrey H C, Lackey RW. Eo-
sinophilic granuloma of the lung. U.S. Armed Forces Med J 1951; 2:1085-93. 2. Marcy TW, Reynolds HY. Pulmonary histiocytosis X. Lung 1985; 163:129-50. 3. Masson RG, Tedeschi LG. Pulmonary eosinophilic granuloma with hilar adenopathy simulating sarco idosis . Ch est 1978; 73:682-3 .
1218
CASE REPORT
4. Friedman PJ, Liebow AA, Sokoloff J. Eosinophilic granuloma of lung. Medicine 1981; 60:385-96.
5. Basset F, Corrin B, Spencer H, et al. Pulmonary histiocytosis X. Am Rev Respir Dis 1978; 118:811-20.
6. Lacronique J, Roth C, Battesti JP, Chretien J . Chest radiological features of pulmonary histiocytosis X. Thorax 1982; 37:104-9. 7. Mottoi M, Helbron D, Kaiserling E, Lennert K. Eosinophilic granuloma of lymph nodes: a variant of histiocytosis X. Histopathology 1980; 4:585-606.
8. Williams JW, Dorfman RF. Lymphadenopathy as the initial manifestation of histiocytosis X. Am J Surg Pathol 1979; 3:405-21. 9. Writing Group of the Histiocyte Society. Histiocytosis syndrome in children. Lancet 1987; 1:208-9.
Fig . 4. Electron micrographs illust rating histiocytes X in the lung (top) (x12,BOO). High magnification of X bodies (bottom) (x56,OOO).
