DIAGNOSTIC DILEMMA Aimee K. Zaas, MD Thomas J. Marrie, MD, Section Editors
Pulmonary Langerhans Cell Histiocytosis with Systemic Features Georgia Thomas, MD,a Renee K. Dixon, MD,b Ann Zimrin, MD,c John Papadimitriou, MD, PhD,d Nirav G. Shah, MDb a
Department of Internal Medicine, bDivision of Pulmonary and Critical Care Medicine, cDepartment of Hematology-Oncology, dDepartment of Pathology, University of Maryland School of Medicine, Baltimore.
PRESENTATION A 42-year-old African-American male smoker in otherwise good health presented to the emergency department with bilateral axillary ulcerated masses, which he initially noticed 1 year previously. The masses were nontender with partially denuded overlying skin.
histiocytes positive for S100, CD1a, and Langerin, consistent with Langerhans cell histiocytosis. Computed tomography of the chest revealed reticular and nodular infiltrates with bilateral cysts (Figure 1). Pulmonary function testing revealed a mild restrictive ventilator defect and a moderate defect in gas transfer. Subsequent bronchoscopy with transbronchial biopsies confirmed pulmonary Langerhans cell histiocytosis (Figures 2 and 3).
ASSESSMENT Axillary skin biopsy showed infiltration of the dermis with lymphocytes, plasma cells, eosinophils, and atypical
Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Nirav G. Shah, MD, Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, 22 S. Greene St, Baltimore, MD 21201. E-mail address: [email protected]
Figure 1
DIAGNOSIS Langerhans cell histiocytosis is a rare condition in which tissues are infiltrated with Langerhans dendritic cells (the primary antigen-presenting cells of the skin), resulting in a wide spectrum of disorders in both children and adults. Langerhans cell histiocytosis in adults is limited predominantly to pulmonary involvement with multisystem disease occurring rarely. Our case illustrates an uncommon finding of pulmonary Langerhans cell histiocytosis with systemic features.
Initial computed tomography of the chest demonstrating bilateral nodules and cysts.
0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.04.029
e8
The American Journal of Medicine, Vol 128, No 10, October 2015
Figure 2 Hematoxylin-eosin stain of the transbronchial biopsy specimen (40 magnification) demonstrating a mixture of eosinophils and Langerhans-type histiocytes.
Paul Langerhans was a German physician who first described the epidermal dendritic “Langerhans” cell in 1868.1 The concept of Langerhans cell histiocytosis was first proposed by Farber in 1941,2 and the disease was called by several names, including eosinophilic granuloma, Letterer-Siwe disease, and Hand-Schüller-Christian disease, until it was renamed as histiocytosis X in 1952 by Lichtenstein.3 The actual number of cases reported of pulmonary Langerhans cell histiocytosis is unknown, and it is thought to be an underdiagnosed condition. In large series, the prevalence has been estimated at 3% to 5% in patients undergoing lung biopsy for evaluation of interstitial lung disease.4 The majority of patients with pulmonary Langerhans cell histiocytosis are asymptomatic smokers whose disease is discovered incidentally on abnormal chest imaging, although patients may present with pneumothoraces,
Figure 3
cough, dyspnea, or constitutional symptoms.5 Extrapulmonary manifestations occur in less than 20% of cases, most commonly with cystic bone lesions, skin involvement, and posterior pituitary involvement with diabetes insipidus. Typical chest computed tomography findings show nodular and cystic abnormalities predominantly in the upper and middle lung fields with relative sparing of the lung bases. Nodules typically characterize early disease, whereas cystic lesions are more dominant in advanced disease and can progress to involve the lower lung zones, with some patients developing honeycombing and fibrosis. Pulmonary function testing reveals an abnormality in only approximately 20% of patients at the time of diagnosis with the most common abnormality being a decrease in diffusion capacity.4 A restrictive pattern is observed frequently early in the disease process, but an obstructive pattern is more common in advanced disease. Although more than 90% of patients are smokers, the degree of obstruction is typically more than what would be expected from cigarette consumption alone. On pathologic examination, the lungs affected by Langerhans cell histiocytosis grossly demonstrate cystic structures on the surface similar in appearance to advanced emphysema. Microscopic examination reveals destructive bronchiolitis with stellate nodules distributed around small airways; these nodules are composed of inflammatory cells—Langerhans cells, plasma cells, lymphocytes, and eosinophils. All affected tissues will show inflammatory cell infiltration with the presence of Langerhans cells, which are characterized by indented nuclei with 1 or 2 nucleoli and relatively abundant eosinophilic cytoplasm. Langerhans cells demonstrate positive immunohistochemical staining for S100, CD1a, and Langerin.4,5 Birbeck granules, rodshaped organelles that participate in receptor-mediated endocytosis and antigen presentation, are also pathognomonic of Langerhans cells when viewed on electron microscopy6 (Figure 4).
S100 and CD1 stains of the transbronchial biopsy specimen revealing Langerhans cells.
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CONCLUSIONS Our patient underwent treatment according to the Langerhans cell histiocytosis-II protocol with prednisone, etoposide, and vinblastine, which improved his lymphadenopathy and lung nodularity, and modestly improved his pulmonary function testing. However, 2 years later he relapsed with axillary lymphadenopathy, dyspnea, and increasing lung nodularity and cysts. He underwent treatment, this time with cytarabine, and his course was complicated by pneumonia and deep venous thrombosis. His disease stabilized on this therapy but did not regress, and he recently restarted another regimen of prednisone, etoposide, and vinblastine. His chest imaging again has shown some improvement, but his lymphadenopathy has not regressed. Figure 4 Electron micrograph of Birbeck granules in Langerhans cell.
MANAGEMENT The pathogenesis of Langerhans cell histiocytosis remains unclear as it continues to be debated whether or not it is a malignant condition. The inflammatory component, spontaneous remissions, and occasional benign clinical course argue for a reactive process; however, the demonstration that Langerhans cells are clonal and recently discovered BRAF mutations point strongly toward a neoplastic disease.7 The majority of patients with localized Langerhans cell histiocytosis typically carry a favorable prognosis with a median survival of 12.5 years from time of diagnosis for only pulmonary disease.4,8 Multisystem Langerhans cell histiocytosis carries a less favorable prognosis and requires treatment with steroids or cytotoxic drugs, although a specific regimen for adults is not well established.7 All patients should be counseled aggressively on smoking cessation. Patients are also at an increased risk of lung cancers and hematologic malignancies, therefore requiring close follow-up.9
References 1. Jolles S. Paul Langerhans. J Clin Pathol. 2002;55:243. 2. Farber S. The nature of “solitary or eosinophilic granuloma” of bone. Am J Pathol. 1941;17:625. 3. Lichtenstein L. Histiocytosis X; integration of eosinophilic granuloma of bone, Letterer-Siwe disease, and Schüller-Christian disease as related manifestations of a single nosologic entity. AMA Archives of Pathology. 1953;56:84-102. 4. Juvet S, Hwang D, Downey G. Rare lung diseases III: pulmonary Langerhans’ cell histiocytosis. Can Respir J. 2010;17:e55-e62. 5. Vassallo R, Ryu JH, Schroeder DR, et al. Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in adults. N Engl J Med. 2002;346:484-490. 6. McDermott R, Ziylan U, Spehner D, et al. Birbeck granules are subdomains of endoscomal recycling compartment in human epidermal Langerhans cells, which form where Langerin accumulates. Mol Biol Cell. 2002;13:317-335. 7. Badalian-Very G, Vergilio J, Fleming M, et al. Pathogenesis of Langerhans cell histiocytosis. Annu Rev Pathol. 2013;8:1-20. 8. Matsuki E, Tsukada Y, Nakaya A, et al. Successful treatment of adult onset Langerhans cell histiocytosis with multi-drug combination therapy. Intern Med. 2011;50:909-914. 9. Wilejto M, Oussama A. Langerhans cell histiocytosis and EdheimChester disease. Curr Opin Rheumatol. 2012;24:90-96.
Pulmonary Langerhans Cell Histiocytosis with Systemic Features Georgia Thomas, MD,a Renee K. Dixon, MD,b Ann Zimrin, MD,c John Papadimitriou, MD, PhD,d Nirav G. Shah, MDb a
Department of Internal Medicine, bDivision of Pulmonary and Critical Care Medicine, cDepartment of Hematology-Oncology, dDepartment of Pathology, University of Maryland School of Medicine, Baltimore.
PRESENTATION A 42-year-old African-American male smoker in otherwise good health presented to the emergency department with bilateral axillary ulcerated masses, which he initially noticed 1 year previously. The masses were nontender with partially denuded overlying skin.
histiocytes positive for S100, CD1a, and Langerin, consistent with Langerhans cell histiocytosis. Computed tomography of the chest revealed reticular and nodular infiltrates with bilateral cysts (Figure 1). Pulmonary function testing revealed a mild restrictive ventilator defect and a moderate defect in gas transfer. Subsequent bronchoscopy with transbronchial biopsies confirmed pulmonary Langerhans cell histiocytosis (Figures 2 and 3).
ASSESSMENT Axillary skin biopsy showed infiltration of the dermis with lymphocytes, plasma cells, eosinophils, and atypical
Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Nirav G. Shah, MD, Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, 22 S. Greene St, Baltimore, MD 21201. E-mail address: [email protected]
Figure 1
DIAGNOSIS Langerhans cell histiocytosis is a rare condition in which tissues are infiltrated with Langerhans dendritic cells (the primary antigen-presenting cells of the skin), resulting in a wide spectrum of disorders in both children and adults. Langerhans cell histiocytosis in adults is limited predominantly to pulmonary involvement with multisystem disease occurring rarely. Our case illustrates an uncommon finding of pulmonary Langerhans cell histiocytosis with systemic features.
Initial computed tomography of the chest demonstrating bilateral nodules and cysts.
0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.04.029
e8
The American Journal of Medicine, Vol 128, No 10, October 2015
Figure 2 Hematoxylin-eosin stain of the transbronchial biopsy specimen (40 magnification) demonstrating a mixture of eosinophils and Langerhans-type histiocytes.
Paul Langerhans was a German physician who first described the epidermal dendritic “Langerhans” cell in 1868.1 The concept of Langerhans cell histiocytosis was first proposed by Farber in 1941,2 and the disease was called by several names, including eosinophilic granuloma, Letterer-Siwe disease, and Hand-Schüller-Christian disease, until it was renamed as histiocytosis X in 1952 by Lichtenstein.3 The actual number of cases reported of pulmonary Langerhans cell histiocytosis is unknown, and it is thought to be an underdiagnosed condition. In large series, the prevalence has been estimated at 3% to 5% in patients undergoing lung biopsy for evaluation of interstitial lung disease.4 The majority of patients with pulmonary Langerhans cell histiocytosis are asymptomatic smokers whose disease is discovered incidentally on abnormal chest imaging, although patients may present with pneumothoraces,
Figure 3
cough, dyspnea, or constitutional symptoms.5 Extrapulmonary manifestations occur in less than 20% of cases, most commonly with cystic bone lesions, skin involvement, and posterior pituitary involvement with diabetes insipidus. Typical chest computed tomography findings show nodular and cystic abnormalities predominantly in the upper and middle lung fields with relative sparing of the lung bases. Nodules typically characterize early disease, whereas cystic lesions are more dominant in advanced disease and can progress to involve the lower lung zones, with some patients developing honeycombing and fibrosis. Pulmonary function testing reveals an abnormality in only approximately 20% of patients at the time of diagnosis with the most common abnormality being a decrease in diffusion capacity.4 A restrictive pattern is observed frequently early in the disease process, but an obstructive pattern is more common in advanced disease. Although more than 90% of patients are smokers, the degree of obstruction is typically more than what would be expected from cigarette consumption alone. On pathologic examination, the lungs affected by Langerhans cell histiocytosis grossly demonstrate cystic structures on the surface similar in appearance to advanced emphysema. Microscopic examination reveals destructive bronchiolitis with stellate nodules distributed around small airways; these nodules are composed of inflammatory cells—Langerhans cells, plasma cells, lymphocytes, and eosinophils. All affected tissues will show inflammatory cell infiltration with the presence of Langerhans cells, which are characterized by indented nuclei with 1 or 2 nucleoli and relatively abundant eosinophilic cytoplasm. Langerhans cells demonstrate positive immunohistochemical staining for S100, CD1a, and Langerin.4,5 Birbeck granules, rodshaped organelles that participate in receptor-mediated endocytosis and antigen presentation, are also pathognomonic of Langerhans cells when viewed on electron microscopy6 (Figure 4).
S100 and CD1 stains of the transbronchial biopsy specimen revealing Langerhans cells.
Thomas et al
Langerhans Cell Histiocytosis
e9
CONCLUSIONS Our patient underwent treatment according to the Langerhans cell histiocytosis-II protocol with prednisone, etoposide, and vinblastine, which improved his lymphadenopathy and lung nodularity, and modestly improved his pulmonary function testing. However, 2 years later he relapsed with axillary lymphadenopathy, dyspnea, and increasing lung nodularity and cysts. He underwent treatment, this time with cytarabine, and his course was complicated by pneumonia and deep venous thrombosis. His disease stabilized on this therapy but did not regress, and he recently restarted another regimen of prednisone, etoposide, and vinblastine. His chest imaging again has shown some improvement, but his lymphadenopathy has not regressed. Figure 4 Electron micrograph of Birbeck granules in Langerhans cell.
MANAGEMENT The pathogenesis of Langerhans cell histiocytosis remains unclear as it continues to be debated whether or not it is a malignant condition. The inflammatory component, spontaneous remissions, and occasional benign clinical course argue for a reactive process; however, the demonstration that Langerhans cells are clonal and recently discovered BRAF mutations point strongly toward a neoplastic disease.7 The majority of patients with localized Langerhans cell histiocytosis typically carry a favorable prognosis with a median survival of 12.5 years from time of diagnosis for only pulmonary disease.4,8 Multisystem Langerhans cell histiocytosis carries a less favorable prognosis and requires treatment with steroids or cytotoxic drugs, although a specific regimen for adults is not well established.7 All patients should be counseled aggressively on smoking cessation. Patients are also at an increased risk of lung cancers and hematologic malignancies, therefore requiring close follow-up.9
References 1. Jolles S. Paul Langerhans. J Clin Pathol. 2002;55:243. 2. Farber S. The nature of “solitary or eosinophilic granuloma” of bone. Am J Pathol. 1941;17:625. 3. Lichtenstein L. Histiocytosis X; integration of eosinophilic granuloma of bone, Letterer-Siwe disease, and Schüller-Christian disease as related manifestations of a single nosologic entity. AMA Archives of Pathology. 1953;56:84-102. 4. Juvet S, Hwang D, Downey G. Rare lung diseases III: pulmonary Langerhans’ cell histiocytosis. Can Respir J. 2010;17:e55-e62. 5. Vassallo R, Ryu JH, Schroeder DR, et al. Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in adults. N Engl J Med. 2002;346:484-490. 6. McDermott R, Ziylan U, Spehner D, et al. Birbeck granules are subdomains of endoscomal recycling compartment in human epidermal Langerhans cells, which form where Langerin accumulates. Mol Biol Cell. 2002;13:317-335. 7. Badalian-Very G, Vergilio J, Fleming M, et al. Pathogenesis of Langerhans cell histiocytosis. Annu Rev Pathol. 2013;8:1-20. 8. Matsuki E, Tsukada Y, Nakaya A, et al. Successful treatment of adult onset Langerhans cell histiocytosis with multi-drug combination therapy. Intern Med. 2011;50:909-914. 9. Wilejto M, Oussama A. Langerhans cell histiocytosis and EdheimChester disease. Curr Opin Rheumatol. 2012;24:90-96.
