Published ahead of print on January 6, 2006, doi:10.1164/rccm.200510-1620CR
© 2006 American Thoracic Society doi: 10.1164/rccm.200510-1620CR
Pulmonary Cystic Disorder Related to Light Chain Deposition DiseaseService d'Anatomie Pathologique and Service de Pneumologie–Hôpital Beaujon, Clichy; Service de Pneumologie–Hôpital Foch, Suresnes; Service d'Anatomie Pathologique–Hôpital Saint-Louis, Service de Médecine Interne–Groupe Hospitalier Pitié-Salpétrière, and Service d'Anatomie Pathologique–Hôpital Européen Georges Pompidou, Paris; Service de Radiologie and Service de Pneumologie–Hôpital Avicenne, Bobigny; and Service de Pneumologie–Hôpital Intercommunal, Créteil, France Correspondence and requests for reprints should be addressed to Magali Colombat, M.D., Service d'Anatomie Pathologique, Hôpital Tenon, 4 Rue de la Chine, 75020 Paris, France. E-mail: colombatm{at}yahoo.fr
Light chain deposition disease (LCDD) is a rare disorder that very uncommonly affects the lung. We report three cases of severe cystic pulmonary LCDD leading to lung transplantation. Such a presentation has never been previously reported. The three patients present with a progressive obstructive pulmonary pattern associated with numerous cysts diffusely distributed in both lungs. The disease was histologically characterized by non–amyloid amorphous deposits in the alveolar walls, the small airways and the vessels. It was associated with emphysematous-like changes and small airway dilation. Monotypic  light chain fixation was demonstrated on the abnormal deposits and along the basement membranes. Electron microscopy revealed coarsely granular electron-dense deposits in the same localizations. Mild extrapulmonary deposits were found in salivary glands in one patient. No immunoproliferative disorder was identified. We conclude that LCDD may primarily affect the lung, present as a pulmonary cystic disorder, and lead to severe respiratory insufficiency.
Key Words: cystic lung disorder • light chain deposition disease • lung transplantation
Light chain deposition disease (LCDD), a rare disease recognized in 1976 by Randall, is characterized by the deposition of a nonfibrillary, amorphous material that does not have We describe three cases of LCDD presenting as a bilateral cystic lung disorder with severe chronic respiratory failure leading to lung transplantation (LT). Such a presentation has never been reported. A confident diagnosis was established in the three cases.
Patient 1 In September 2001, a 33-yr-old woman presented with a first bilateral spontaneous pneumothorax. She was a former light smoker (1 pack-year) and worked in a bakery. Thoracic computed tomography (CT) scan demonstrated round thin-walled cystic airspaces measuring up to 2 cm and distributed in both lungs except the upper zones (Figure 1A). Hilar and mediastinal lymph nodes were not enlarged. No abnormality was detected on the abdominal CT scan. Based on clinical and radiologic data, a presumptive diagnosis of Langerhans' cell histiocytosis (LCH) or lymphangioleiomyomatosis (LAM) was proposed. During the following years, she experienced three additional episodes of pneumothorax. Her respiratory status progressively worsened, requiring permanent oxygen therapy. The number of cysts significantly increased (Figure 1B), and the cysts were associated with linear opacities, irregular shaped nodules and small areas of consolidation (Figure 1B). Small bilateral hilar lymphadenopathies appeared. In November 2003, the patient was referred for LT because of severe respiratory insufficiency (Table 1). Right-heart catheterization did not demonstrate pulmonary hypertension, and cardiac output was normal. Bilateral LT was performed in July 2004. The diagnosis of pulmonary LCDD was made after pathologic analysis of the explanted lungs. The postoperative course was uneventful. No monoclonal peak was detected on serum protein electrophoresis. The concentration of free light chains and the free light chains / ratio, obtained from frozen serum samples stored before transplantation, were 6 and 3 times the normal value, respectively. Three months after LT, these values normalized. Hepatic and renal functions were normal. Proteinuria was absent. Salivary gland biopsy demonstrated mild light chain deposits in the vessel walls and epithelial basement membranes. Bone marrow biopsy did not show plasmocytosis and light chain deposits. The final diagnosis was pulmonary LCDD involving the lung. The patient is well 18 mo after LT.
Patient 2 A 36-yr-old woman was first evaluated in June 1998 for exertional dyspnea associated with dry cough progressing for the last 8 yr. She had not smoked or had any occupational or environment exposures. Physical examination was normal. Thoracic CT scan demonstrated round thin-walled cystic airspaces measuring up to 2 cm and distributed in both lungs (Figure 1C). An open lung biopsy of the right upper and middle lobe was performed. The pathologic analysis demonstrated a pulmonary LCDD with cyst formations. There was no monoclonal peak on serum protein electrophoresis. Hepatic and renal function was normal. No abnormality was found on cardiac echocardiography. Cutaneous, salivary gland, duodenal, rectal, and medullar biopsies did not show light chain deposit. A bone marrow specimen did not show plasmocytosis. Despite treatment with high doses of steroids and autologous peripheral blood stem cell transplantation, dyspnea worsened and radiologic manifestations rapidly progressed. The number of cysts significantly increased (Figure 1D) and became confluent. The lesions were diffusely distributed throughout all lung zones. In November 2000, the patient was referred for LT because of severe respiratory insufficiency (Table 1). Right-heart catheterization did not demonstrate pulmonary hypertension. Cardiac output was within normal range. Bilateral LT was performed in November 2001. No major postoperative complication occurred, and the patient is well 4 yr later without recurrence.
Patient 3
Pathologic Findings Macroscopically, the overall lung size in Patients 1 and 2 was normal and the pleural surface was smooth. The cut surface showed diffuse randomly distributed thin-walled cystic airspaces measuring from a few millimeters to 3 cm. In addition, few irregular shaped nodules up to 2 cm were found in Patient 1.
Microscopic features were very similar in the three patients. The main finding consisted of patchy deposition of an amorphous eosinophilic material in alveolar walls, small airways, and vessels (Figures 2A and 2B). These deposits were most often surrounded by a foreign-body giant cell reaction (Figure 2C). Emphysematous-like changes were present at the edge or at distance of the deposits. Bronchioles sometimes containing deposits within their walls were dilated especially in Patient 2. The nodular areas observed on macroscopic examination in Patient 1 corresponded to quite large zones of lung parenchyma replaced by the same eosinophilic deposits with entrapment and narrowing of airways. Pulmonary arteries and veins exhibited marked intimal fibrous thickening. Iron stain was negative. Scattered lymphoid aggregates and foci with an appreciable number of cytologic normal-appearing plasma cells were present. In the explanted specimens, eosinophilic deposits also involved peribronchial and hilar lymph nodes. The Congo red staining did not display apple-green birefringence under polarized light. Immunofluorescence of frozen tissue disclosed positivity for
This report mainly demonstrates that LCDD may (1) primarily affect the lungs, (2) present as a cystic disease resembling LAM and LCH on radiologic grounds, and (3) lead to severe respiratory insufficiency.
LCDD, as with light chain (AL) amyloidosis is characterized by the deposition of monotypic immunoglobulin light chains deposits in various tissues and organs. Although LCDD and AL amyloidosis are distinct entities, they share some common features. Microscopically, the deposits appear very similar as an amorphous, eosinophilic, and extracellular material with a minor accompanying inflammatory infiltrate composed of lymphocytes, plasma cells, and multinucleated histiocytes (5). The deposits have a predilection for the kidney and the heart in both entities. Moreover, LCDD and amyloidosis are frequently associated with an underlying hematologic condition, especially multiple myeloma (2, 3). However, they differ in two points: (1) the deposits in LCDD lack apple green birefringence with Congo red stain and are mostly composed of Apart from renal, liver, and cardiac involvement, little is known about LCDD in other organs, including the lung. Clinical evidence of respiratory failure has been occasionally described (6). In the literature, LCDD involving the lungs mostly manifests as nodular lesions of various sizes. Only seven patients with pulmonary nodular-type LCDD have been reported in the literature (6–11). The pulmonary nodules were multiple and bilateral in three patients (6, 7, 11) and unique in three other patients (7, 9). In the seventh patient, the lesion consisted in a main pulmonary mass with several nodules in regional lymph nodes and pleura (8). An underlying hematologic condition was detected in four patients: lung plasmocytoma in two patients and lymphoplasmacytic lymphoma and serum monoclonal peak in one each (6–9). Extrapulmonary deposition of light chains was only found in one patient, but the investigations were not extensive (6). Finally, pulmonary interstitial infiltration may be recognized at autopsy of patients with systemic LCDD (12).
LCDD presenting as a pulmonary cystic disorder leading to severe respiratory failure as in our three patients has never been previously described. Histologic findings in these cases were very similar with monotypic
In our patients presenting with acquired thin-walled pulmonary cysts, the differential diagnosis included LAM, LCH, amyloidosis, and lymphoid interstitial pneumonia. The occurrence of a cystic lung disease in a man virtually excludes LAM, as in Patient 3. The absence of pneumothorax, pleural effusion, or hemoptysis, in Patients 2 and 3, makes the diagnosis of LAM less likely. Furthermore, the cysts are characteristically round in LAM, and are not accompanied by nodules except in the rare context of tuberous sclerosis complex (13). LCH can also induce lung cyst formation. It usually occurs in smokers, which is not the case in our patients. The cysts are most commonly associated with stellate nodules and have a centrilobular distribution (14). Centrilobular distribution of the lesions on CT scan was not obvious in our patients, and nodules were only found in Patient 1. Amyloidosis rarely manifests as a pulmonary cystic disorder. Ohdama and colleagues have described, in an asymptomatic woman, a primary diffuse alveolar septal amyloidosis associated with multiple thin-walled cysts measuring up to 1.5 cm (15). In any case, the definitive distinction between amyloidosis and LCDD is based on microscopic examination with Congo red staining, immunofluorescence study using anti-
In conclusion, this study illustrates that LCDD may present as a primary pulmonary cystic disorder leading to an obstructive pulmonary chronic failure. In this context, the diagnosis of LCDD might be suspected either when the clinical and radiologic presentation is not typical for LAM or LCH or when a monoclonal free light chain, especially
The authors thank Dr. E. Longchamp, Dr. P. Aucouturier, Prof. J.C. Brouet, Prof. F. Jaubert, Dr. O. Brugière, and Prof. G. Lesèche for their help in the preparation of the manuscript.
Originally Published in Press as DOI: 10.1164/rccm.200510-1620CR on January 6, 2006 Conflict of Interest Statement: M.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. O.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.B. has participated as a speaker in scientific courses (CT in infiltrative lung diseases) organized and financed by AstraZeneca. D.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form October 17, 2005; accepted in final form January 3, 2006
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ABSTRACT
CASE REPORTS
-pleated sheet configuration and consequently does not bind Congo red as amyloidosis (
