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A 22-Year-Old Nonsmoker With Diffuse Cystic Lung DiseaseNonsmoking Woman With Diffuse Cystic Lung Disease FREE TO VIEW

Kimber Foust, MD; Jeffrey Albores, MD; Gregory A. Fishbein, MD; Scott Genshaft, MD; Tisha Wang, MD
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine (Drs Foust, Albores, and Wang), the Department of Pathology (Dr Fishbein), and the Department of Radiology (Dr Genshaft), David Geffen School of Medicine at UCLA, Los Angeles, CA.

CORRESPONDENCE TO: Jeffrey Albores, MD, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Room 37-131 CHS, Los Angeles, CA 90095-1690; e-mail: jeffalbores@yahoo.com


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(1):e18-e21. doi:10.1378/chest.14-2301
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Published online

A 22-year-old previously healthy woman was evaluated in pulmonary clinic for shortness of breath and cough that had been slowly progressive over 3 months. She otherwise reported being fully functional and attended her college graduation a week prior to evaluation. She had no history of smoking, illicit drug use, connective tissue disease, or noxious exposures.

Figures in this Article

Vital signs were as follows: BP, 120/80 mm Hg; pulse, 120 beats/min; respirations, 24 breaths/min; and oxygen saturation as measured by pulse oximetry on ambient air, 95% at rest and 85% on ambulation. Lung examination was significant for moderately diminished breath sounds and scattered rhonchi on both lung fields. There was no clubbing, cyanosis, or edema in her extremities.

Blood count, metabolic panel, and rheumatologic serologies were all unremarkable. Pulmonary function tests showed a severe restrictive defect with moderate diffusion impairment. Chest radiograph showed diffuse large bilateral cystic changes within both lungs (Fig 1). Subsequent chest CT scan revealed diffuse irregular thin- and thick-walled cysts with upper and middle lung zone predominance (Fig 2). A surgical lung biopsy was recommended for definitive pathologic diagnosis, but the patient deteriorated within 10 days of initial evaluation. She was admitted to the ICU for acute hypoxemic respiratory failure and pneumothorax requiring chest tube placement and mechanical ventilatory support. Empirical high-dose corticosteroids were initiated, but unfortunately she went into pulseless electrical activity arrest and was unable to be resuscitated. An autopsy was obtained. On microscopic examination of the lungs, there was dense cellular inflammation within and surrounding bronchi and bronchioles. Immunohistochemical stains showed an inflammatory infiltrate strongly positive for CD1a and S-100 protein (Fig 3).

Figure Jump LinkFigure 1 –  Chest radiograph showing diffuse large bilateral cystic changes within both lungs.Grahic Jump Location
Figure Jump LinkFigure 2 –  A-D, Serial transverse cuts of chest CT scan showing irregular thin- and thick-walled cysts, some large and consisting of several coalescent cysts, present in both lungs, with upper and middle lung zone predominance and relative sparing of the lung bases.Grahic Jump Location
Figure Jump LinkFigure 3 –  A, Low-magnification hematoxylin-eosin (H&E) stain of a pulmonary nodule consisting of mixed inflammatory cells including numerous cells with granular cytoplasm (magnification × 40). B, High-magnification H&E stain showing prominent scattered eosinophils (arrows) (magnification × 200). C, High-magnification H&E stain showing cells with abundant cytoplasm, indented nuclear membranes, and grooved “coffee bean” nuclei (magnification × 400). D, Cells are immunoreactive for CD1a (magnification × 100) and S-100 protein (not shown).Grahic Jump Location
What is the diagnosis?
Diagnosis: Pulmonary Langerhans cell histiocytosis in a nonsmoker

Pulmonary Langerhans cell histiocytosis (PLCH) (also called eosinophilic granuloma of the lung or pulmonary histiocytosis X) is a rare lung disease that is typically, but not invariably, associated with smoking. Nearly all affected individuals have a history of cigarette smoking; hence, tobacco smoke is believed to be an etiologic factor. In 15% of cases, extrapulmonary manifestations are present. In adults with PLCH, the two most common extrapulmonary manifestations are hypothalamic involvement with diabetes insipidus and cystic bone lesions. Most cases occur sporadically in young adults with no clear sex predilection. PLCH is characterized by the accumulation of Langerhans cells along the small airways of the lung. Langerhans cells originate from the monocyte-macrophage line and are distinguished by the presence of Birbeck granules and staining for the S-100 protein, CD1a, and human leukocyte antigen-DR.

These collections of Langerhans cells form cellular nodules. The nodules, generally 1 to 5 mm in size, are typically a mixture of Langerhans cells, plasma cells, lymphocytes, fibroblasts, and pigmented alveolar macrophages. The nodules then progress to a mixed cellular and fibrotic nodule and finally a fibrotic nodule. The fibrotic nodules are stellate in configuration and may coalesce with adjacent nodules. The cysts arise from destruction of the bronchiolar walls by the granulomatous reaction, with subsequent dilatation of the small airway lumen.

Clinical features frequently include nonproductive cough, dyspnea, and spontaneous pneumothorax, although patients can be completely asymptomatic at the time of presentation. Pulmonary function is variable, but reduced diffusion capacity is the most frequently seen abnormality. As the disease progresses and fibrotic changes appear, a predominantly restrictive pattern may develop. Airflow obstruction and hyperinflation occur in a minority of patients, typically in patients with advanced cystic disease. Many patients manifest a combined restrictive and obstructive pattern.

Typical chest radiograph findings include a micronodular or reticulonodular infiltration that is generally symmetric, bilateral, and predominantly affecting the upper and middle lung zones. Although the degree of cyst formation is often underappreciated by routine chest radiography, with worsening disease cystic changes can be evident. High-resolution chest CT scan is a useful tool in the evaluation of PLCH and in the appropriate clinical context may allow a presumptive diagnosis—classically a combination of multiple cysts and nodules with an upper to middle lung zone predominance and interstitial thickening in a young smoker. Nodules are seen in the early stages of the disease, with the development of cystic lesions as the disease progresses. The nodules can be well- or ill-defined, occasionally large and bizarrely shaped. Cysts are generally < 20 mm in size and are thin walled in nature. Honeycombing can be seen in advanced disease. Fluorodeoxyglucose (FDG)-PET scans may show increased uptake in patients with PLCH. Positive FDG-PET scans are more likely in patients with early disease associated with predominantly nodular chest CT scan findings, and negative FDG-PET scans are more likely to have a cystic pattern and fewer nodules suggesting later disease.

The gold standard for diagnosis of PLCH is via a surgical lung biopsy showing Langerhans cells (cells with abundant eosinophilic cytoplasm and grooved nuclei with indented nuclear membranes) with a bronchiolocentric distribution, Birbeck granules (pentalaminar intracytoplasmic structures) on electron microscopy, and positive immunohistochemical staining for CD1a and S-100 protein. Bronchoscopy with BAL and transbronchial biopsies may also be considered. BAL fluid should be evaluated for the presence of Langerhans cells by staining with antibodies to CD1a. When the presence of Langerhans cells in the BAL is > 5%, the diagnosis is likely. Transbronchial biopsies can provide diagnostic data in 10% to 50% of patients with PLCH and may be considered as the initial diagnostic procedure of choice.

Treatment revolves around smoking cessation and oftentimes this is the only intervention needed to stabilize symptoms. For patients with progressive or symptomatic disease, corticosteroids are often prescribed, although there are neither controlled treatment trials nor evidence of efficacy beyond anecdotal reports. Although corticosteroids may possibly have a role in the early, nodular stage of the disease, it is exceedingly unlikely that they are efficacious with advanced cystic disease. Other immunosuppressive agents have been used in case reports and series, including vinblastine, methotrexate, cyclophosphamide, etoposide, and chlorodeoxyadenosine. A significant improvement in cystic lung changes, dyspnea, and lung function has been seen with the use of chlorodeoxyadenosine, a purine nucleoside analog. Clinicians should also be aware of the increased risk of pneumothorax in this patient population. Conservative therapy may be used to treat small pneumothoraces, but pleurodesis should be considered for recurrent events or large pneumothoraces. Patients should also be screened for pulmonary hypertension, which becomes increasingly common as the disease progresses and is associated with a poorer prognosis.

The prognosis for PLCH is generally favorable in the majority of cases, but there is evidence that these patients have a shorter survival than members of the general population. In addition, there is a subgroup of patients who develop progressive disease. In these patients a variety of factors have been identified, including extremes of age, multisystem involvement, prolonged constitutional symptoms, extensive cysts and honeycombing on imaging, a markedly reduced diffusing capacity, prolonged treatment with corticosteroids, and pulmonary hypertension. As a last resort, lung transplant is an option for those with progressive disease despite smoking cessation and trials of immunosuppression, with survival rates posttransplant comparable to other patient populations. Patients with PLCH have also been found to have an increased incidence of lymphoma and other hematologic abnormalities, although it is unclear whether this is due to a stem cell defect in cells of hematologic lineage, toxicity from immunosuppression, or a tobacco effect.

Clinical Course

The microscopic and immunohistochemical findings confirmed a diagnosis of PLCH. Additionally, multifocal pulmonary thromboemboli were seen that likely contributed to this patient’s pulseless electrical activity arrest and death.

  • 1. PLCH is associated with cigarette smoking in the majority of cases but rarely can occur in never-smokers.

  • 2. The radiographic findings associated with PLCH reflect the stage of the disease, with predominantly nodular opacities in the early stages evolving to predominantly cysts in the later stages. These radiographic changes typically have an upper and middle lung zone distribution.

  • 3. Langerhans cells can be identified through immunohistochemical staining positive for CD1a and S-100 protein.

  • 4. Smoking cessation is central in the treatment of PLCH.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Delobbe A, Durieu J, Duhamel A, Wallaert B. Determinants of survival in pulmonary Langerhans’ cell granulomatosis (histiocytosis X). Groupe d’Etude en Pathologie Interstitielle de la Société de Pathologie Thoracique du Nord. Eur Respir J. 1996;9(10):2002-2006.
 
Kambouchner M, Basset F, Marchal J, Uhl JF, Hance AJ, Soler P. Three-dimensional characterization of pathologic lesions in pulmonary Langerhans cell histiocytosis. Am J Respir Crit Care Med. 2002;166(11):1483-1490.
 
Vassallo R, Ryu JH, Schroeder DR, Decker PA, Limper AH. Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in adults. N Engl J Med. 2002;346(7):484-490.
 
Sundar KM, Gosselin MV, Chung HL, Cahill BC. Pulmonary Langerhans cell histiocytosis: emerging concepts in pathobiology, radiology, and clinical evolution of disease. Chest. 2003;123(5):1673-1683.
 
Mendez JL, Nadrous HF, Vassallo R, Decker PA, Ryu JH. Pneumothorax in pulmonary Langerhans cell histiocytosis. Chest. 2004;125(3):1028-1032.
 
Krajicek BJ, Ryu JH, Hartman TE, Lowe VJ, Vassallo R. Abnormal fluorodeoxyglucose PET in pulmonary Langerhans cell histiocytosis. Chest. 2009;135(6):1542-1549.
 
Lorillon G, Bergeron A, Detourmignies L, et al. Cladribine is effective against cystic pulmonary Langerhans cell histiocytosis. Am J Respir Crit Care Med. 2012;186(9):930-932.
 
Baqir M, Vassallo R, Maldonado F, Yi ES, Ryu JH. Utility of bronchoscopy in pulmonary Langerhans cell histiocytosis. J Bronchology Interv Pulmonol. 2013;20(4):309-312.
 

Figures

Figure Jump LinkFigure 1 –  Chest radiograph showing diffuse large bilateral cystic changes within both lungs.Grahic Jump Location
Figure Jump LinkFigure 2 –  A-D, Serial transverse cuts of chest CT scan showing irregular thin- and thick-walled cysts, some large and consisting of several coalescent cysts, present in both lungs, with upper and middle lung zone predominance and relative sparing of the lung bases.Grahic Jump Location
Figure Jump LinkFigure 3 –  A, Low-magnification hematoxylin-eosin (H&E) stain of a pulmonary nodule consisting of mixed inflammatory cells including numerous cells with granular cytoplasm (magnification × 40). B, High-magnification H&E stain showing prominent scattered eosinophils (arrows) (magnification × 200). C, High-magnification H&E stain showing cells with abundant cytoplasm, indented nuclear membranes, and grooved “coffee bean” nuclei (magnification × 400). D, Cells are immunoreactive for CD1a (magnification × 100) and S-100 protein (not shown).Grahic Jump Location

Tables

Suggested Readings

Delobbe A, Durieu J, Duhamel A, Wallaert B. Determinants of survival in pulmonary Langerhans’ cell granulomatosis (histiocytosis X). Groupe d’Etude en Pathologie Interstitielle de la Société de Pathologie Thoracique du Nord. Eur Respir J. 1996;9(10):2002-2006.
 
Kambouchner M, Basset F, Marchal J, Uhl JF, Hance AJ, Soler P. Three-dimensional characterization of pathologic lesions in pulmonary Langerhans cell histiocytosis. Am J Respir Crit Care Med. 2002;166(11):1483-1490.
 
Vassallo R, Ryu JH, Schroeder DR, Decker PA, Limper AH. Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in adults. N Engl J Med. 2002;346(7):484-490.
 
Sundar KM, Gosselin MV, Chung HL, Cahill BC. Pulmonary Langerhans cell histiocytosis: emerging concepts in pathobiology, radiology, and clinical evolution of disease. Chest. 2003;123(5):1673-1683.
 
Mendez JL, Nadrous HF, Vassallo R, Decker PA, Ryu JH. Pneumothorax in pulmonary Langerhans cell histiocytosis. Chest. 2004;125(3):1028-1032.
 
Krajicek BJ, Ryu JH, Hartman TE, Lowe VJ, Vassallo R. Abnormal fluorodeoxyglucose PET in pulmonary Langerhans cell histiocytosis. Chest. 2009;135(6):1542-1549.
 
Lorillon G, Bergeron A, Detourmignies L, et al. Cladribine is effective against cystic pulmonary Langerhans cell histiocytosis. Am J Respir Crit Care Med. 2012;186(9):930-932.
 
Baqir M, Vassallo R, Maldonado F, Yi ES, Ryu JH. Utility of bronchoscopy in pulmonary Langerhans cell histiocytosis. J Bronchology Interv Pulmonol. 2013;20(4):309-312.
 
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