Pulmonary Medicine

Pulmonary Langerhans Cell Histiocytosis

What every physician needs to know:

Pulmonary Langerhans cell histiocytosis (PLCH) encountered in adults is usually a smoking-related interstitial lung disease that is characterized by proliferation of Langerhans cells and associated nodular and cystic changes in the lung parenchyma.

Classification

PLCH encountered in adults should be distinguished from other forms of Langerhans cell histiocytosis, particularly those encountered in children, which are usually multi-system clonal disorders.

Are you sure your patient has pulmonary Langerhans cell histiocytosis? What should you expect to find?

Approximately two-thirds of patients with PLCH are symptomatic at presentation, with the most common symptoms consisting of dyspnea and cough. Constitutional symptoms, including fever, sweats, and weight loss, are encountered in 15-20 percent of patients. Pneumothorax is the mode of presentation in about 15 percent of patients. Uncommon features include diabestes insipidus, skin lesions, and pain that is due to bone involvement.

Beware: there are other diseases that can mimic pulmonary Langerhans cell histiocytosis:

Other diseases that can be associated with cystic changes in the lungs and that can be confused with PLCH include pulmonary lymphangioleiomyomatosis (LAM), Birt-Hogg-Dube syndrome, lymphoid interstitial pneumonia (LIP), and centrilobular emphysema.

How and/or why did the patient develop pulmonary Langerhans cell histiocytosis?

More than 90 percent of adults diagnosed with PLCH are current or previous cigarette smokers. Age at the time of presentation is usually twenty to fifty years. There is no gender predilection.

Which individuals are at greatest risk of developing pulmonary Langerhans cell histiocytosis?

The main risk factor for developing adult PLCH is cigarette smoking. No other risk factors have been identified.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Routine laboratory studies are not useful in the diagnosis of PLCH.

What imaging studies will be helpful in making or excluding the diagnosis of pulmonary Langerhans cell histiocytosis?

High-resolution CT scan of the chest should be obtained in any patient suspected of PLCH who demonstrates nodular and/or irregularly shaped cystic lesions in the upper- and mid-lung zones ( Figure 1A) with relative sparing of the lung bases (Figure 1B) (Figure 2). Architectural distortion consisting of coarse reticular opacities are commonly seen in the intervening lung parenchyma. By contrast, cystic lesions of pulmonary lymphangioleiomyomatosis (LAM) are generally round and are diffusely distributed throughout the lungs with no zonal predominance or sparing.

Figure 1A.

A high-resolution CT image of the upper lung field in a forty-eight-year-old female smoker with PLCH reveals cystic and nodular lesions in both lungs.

Figure 1B.

A high-resolution CT image of the upper lung field in a forty-eight-year-old female smoker with PLCH demonstrates relative sparing of the lung bases.

Figure 2.

A high-resolution CT coronal image in a thirty-two-year-old female smoker with PLCH demonstrates advanced irregular cystic changes in the upper- and mid-lung fields with relative sparing of the lung bases.

Chest radiography, which is almost always abnormal, reveals interstitial lung infiltrates predominantly in the upper- and mid-lung fields. However, the nodules and cysts characteristic of PLCH are difficult to discern on chest radiography.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of pulmonary Langerhans cell histiocytosis?

Pulmonary function tests reveal variable results that have an obstructive or mixed pattern more often than a restrictive pattern. About 70 percent of with PLCH have a reduced diffusing capacity measurement. Up to 20 percent of patients may have normal pulmonary function results at presentation.

What diagnostic procedures will be helpful in making or excluding the diagnosis of pulmonary Langerhans cell histiocytosis?

Bronchoscopy with transbronchial biopsy and bronchoalveolar lavage (BAL) may confirm the diagnosis in 15-40 percent of patients with PLCH. The presence of at least 5 percent CD1a-positive cells (Langerhans cells) is highly suggestive of PLCH.

If bronchoscopic specimens do not provide confirmatory evidence for the diagnosis of PLCH, surgical lung biopsy may be needed (Figure 3).

Figure 3.

A high-power magnification view of PLCH histopathology demonstrating infiltration with Langerhans cells (characterized by pale staining cytoplasm and elongated nuclei with delicate folds and clefts and large nucleoli) and scattered eosinophils.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of pulmonary Langerhans cell histiocytosis?

Immunohistochemical staining for CD1a antigen, S-100, and langerin are helpful in identifying Langerhans cells in the pathologic lesion.

If you decide the patient has pulmonary Langerhans cell histiocytosis, how should the patient be managed?

Patients diagnosed with PLCH who are still smoking cigarettes must cease smoking promptly. Corticosteroid therapy, typically in the form of oral prednisone 40-60 mg per day with slow tapering over a course of several months, has been employed but is of uncertain benefit in treating PLCH. Chemotherapy agents like 2-chlorodeoxyadenosine, (2-CDA or cladribine), vinblastine, cyclophosphamide, and methotrexate have also been used, but their therapeutic role in PLCH remains unclear.

Lung transplantation is an option for patients with progressive pulmonary disease resulting in severe pulmonary impairment and symptoms. Recurrence of PLCH has been noted in 20 percent of patients who have undergone lung transplantation.

Smoking cessation, which is the most effective method of managing adult PLCH, often requires the use of nicotine replacement along with other pharmacologic therapies (e.g., bupropion, varenicline) and counseling. Corticosteroid therapy may provide modest benefit in some patients with PLCH, but it risks well-known adverse effects associated with long-term therapy, including immunosuppression, osteoporosis, and metabolic effects. Chemotherapy agents are associated with myelosuppression, renal and hepatic toxicity, and other adverse effects related to specific agents.

What is the prognosis for patients managed in the recommended ways?

With successful smoking cessation, most patients experience stabilization or improvement of their lung disease. Continuing exposure to cigarette smoke usually results in progressive lung disease with increasing risk of complications like pulmonary hypertension, hypoxemia, and respiratory failure.

What other considerations exist for patients with pulmonary Langerhans cell histiocytosis?

Pulmonary hypertension in patients with PLCH may be amenable to vasomodulator therapy, such as sildenafil or bosentan.

The recurrence rate in patients who experience spontaneous pneumothorax associated with PLCH is relatively high at about 60 percent. Pleurodesis, preferably surgical, is generally recommended to prevent recurrent pneumothorax.

What’s the evidence?

Vassallo, R, Ryu, JH. "Pulmonary Langerhans' cell histiocytosis". Clinics in Chest Medicine. vol. 25. 2004. pp. 561-71.

This review provides an overview of PLCH.

Yousem, SA, Colby, TV, Chen, YY, Chen, WG, Weiss, LM. "Pulmonary Langerhans' cell histiocytosis: molecular analysis of clonality". Am J Surg Pathol. vol. 25. 2001. pp. 630-636.

Molecular analysis suggests that, in contrast to multisystem Langerhans cell histiocytosis, PLCH is primarily a reactive process.

Allen, TC. "Pulmonary Langerhans cell histiocytosis and other pulmonary histiocytic diseases: a review". Arch Pathol Lab Med. vol. 132. 2008. pp. 1171 -81.

This review discusses histopathologic features of PLCH and other histiocytic lesions.

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. vol. 166. 2002. pp. 1483-1490.

Three-dimensional analysis of histopathology suggests PLCH is a bronchiolocentric lesion.

Vassallo, R, Jensen, EA, Colby, TV, Ryu, JH, Douglas, WW, Hartman, TE. "The overlap between respiratory bronchiolitis and desquamative interstitial pneumonia in pulmonary Langerhans cell histiocytosis: high-resolution CT, histologic, and functional correlations". Chest. vol. 124. 2003. pp. 1199-1205.

Histopathologic evidence of respiratory bronchiolitis and desquamative interstitial pneumonia related to smoking is commonly found in patients diagnosed with PLCH.

Vassallo, R, Ryu, JH, Schroeder, DR, Decker, PA, Limper, AH. "Clinical outcomes of pulmonary Langerhans-cell histiocytosis in adults". N Engl J Med. vol. 346. 2002. pp. 484-490.

A study of 102 adults with PLCH and their clinical course.

Friedman, PJ, Liebow, AA, Sokoloff, J. "Eosinophilic granuloma of lung: clinical aspects of primary histiocytosis in the adult". Medicine (Baltimore). vol. 60. 1981. pp. 385-396.

Analysis of epidemiologic, clinical, and radiographic features of 100 adults with PLCH and associated clinical course.

Mendez, JL, Nadrous, HF, Vassallo, R, Decker, PA, Ryu, JH. "Pneumothorax in pulmonary Langerhans cell histiocytosis". Chest. vol. 125. 2004. pp. 1028-1032.

In this study of 106 patients with PLCH, 16 percent had experienced pneumothorax with a recurrence rate of 58 percent. Surgical pleurodesis was effective in preventing recurrent pneumothorax.

Chaowalit, N, Pellikka, PA, Decker, PA, Aubry, MC, Krowka, MJ, Ryu, JH. "Echocardiographic and clinical characteristics of pulmonary hypertension complicating pulmonary Langerhans cell histiocytosis.". Mayo Clin Proc. vol. 79. 2004. pp. 1269-1275.

Severe pulmonary hypertension that is not necessarily related to advanced lung disease can occur in patients with PLCH and adversely impact the chances of survival.

Mogulkoc, N, Veral, A, Bishop, PW, Bayindir, U, Pickering, CA, Egan, JJ. "Pulmonary Langerhans cell histiocytosis: radiologic resolution following smoking cessation". Chest. vol. 115. 1999. pp. 1452-1455.

Report of two adults with PLCH who experienced radiologic improvement following smoking cessation.

Koyama, M, Johkoh, T, Honda, O, Tsubamoto, M, Kozuka, T, Tomiyama, N. "Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients.". AJR. vol. 180. 2003. pp. 827-835.

Although cystic lung disease of PLCH often has a characteristic appearance, there is some overlap with other cystic lung diseases.

Bonelli, FS, Hartman, TE, Swensen, SJ, Sherrick, A. "Accuracy of high-resolution CT in diagnosing lung diseases". AJR Am J Roentgenol. vol. 170. 1998. pp. 1507-1512.

The distribution of cystic changes in PLCH differs from that of pulmonary lymphangioleiomyomatosis.

Brauner, MW, Grenier, P, Tijani, K, Battesti, JP, Valeyre, D. "Pulmonary Langerhans cell histiocytosis: evolution of lesions on CT scans". Radiology. vol. 204. 1997. pp. 497-502.

Nodular lesions seen on HRCT appear to be active lesions and either to evolve into cysts or to regress.

Basset, F, Corrin, B, Spencer, H, Lacronique, J, Roth, C, Soler, P. "Pulmonary histiocytosis X". Am Rev Respir Dis. vol. 118. 1978. pp. 811-820.

Although Langerhans cells can be found in other disorders, including idiopathic pulmonary fibrosis, the presence of at least 5 percent CD1a-positive cells in the BAL fluid was found to be highly specific for PLCH.

Von Essen, S, West, W, Sitorius, M, Rennard, SI. "Complete resolution of roentgenographic changes in a patient with pulmonary histiocytosis X". Chest. vol. 98. 1990. pp. 765-767.

A smoker with PLCH had complete resolution of chest radiographic abnormalities following smoking cessation.

Aerni, MR, Aubry, MC, Myers, JL, Vassallo, R. "Complete remission of nodular pulmonary Langerhans cell histiocytosis lesions induced by 2-chlorodeoxyadenosine in a non-smoker". Respir Med. vol. 102. 2008. pp. 316-319.

A case report of a sixty-six-year-old man with multisystem LCH who experienced resolution of lung involvement with 2-chorodeoxyadenosine (cladribine) therapy.

Saven, A, Burian, C. "Cladribine activity in adult Langerhans-cell histiocytosis". Blood. vol. 93. 1999. pp. 4125-4130.

A study of thirteen LCH patients, including six with pulmonary involvement, suggests that cladribine has efficacy in LCH encountered in adults.

Dauriat, G, Mal, H, Thabut, G, Mornex, J-F, Bertocchi, M, Tronc, F. "Lung transplantation for pulmonary Langerhans' cell histiocytosis: a multicenter analysis.". Transplantation. vol. 81. 2006. pp. 746-750.

A study of thirty-nine PLCH patients who underwent lung transplantation revealed a post-transplant survival rate comparable to other lung transplant patients and a PLCH recurrence rate of 20 percent.

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