Diagnosis: Langerhans' cell histiocytosis (LCH)
Comment: There was no evidence of intravenous drug use or crack cocaine smoking in the lung biopsy.
Discussion: Pulmonary Langerhans' Cell Histiocytosis (LCH)
Introduction: LCH is a rare entity that involves single organs or multiple organs/tissues. Lesions are composed predominantly of cells resembling the normal Langerhans' cell (LC), which is present in skin and mucous membranes, including the respiratory mucosa. In the past, the terms histiocytosis X, eosinophilic granuloma, Hand-Schüller-Christian disease, and Langerhans' cell granulomatosis have been used to designate the disease or its various subtypes. The histologic lesion is the LC nodule, which is composed of LCs and variable numbers of lymphocytes and eosinophils. The LC is derived from CD34+ bone marrow stem cells, and its differentiation is promoted by GM-CSF, TNF-alpha, IL-3, and IL-4. It functions primarily as an antigen-presenting cell and not as a phagocyte like the CD34-derived macrophage, which is also a type of histiocyte .
Clinical features of pulmonary LCH: Men predominate in some series [2,3], women in others , and probably the sexes are about equally affected. More than 90% are cigarette smokers, and the others often have a history of smoking [2,5]. The peak incidence is in the 3rd and 4th decades. Patients present with cough, dyspnea, chest pain (pneumothorax), hemoptysis, or wheeze; about 20% are asymptomatic. Malaise, weight loss, or fever occur in 1/3 of patients. Pulmonary function tests show restriction, obstruction, or a normal pattern . Exercise may be limited by vascular dysfunction , and pulmonary hypertension, sometimes steroid responsive, can develop [7-9]. Multifocal disease may occur in 18% [3,5]. A relapsing course has been described in 4 patients, with recurrences 7 mo to 7.5 y after the initial presentation .
Radiographic changes: Typically, on plain films disease is bilateral in the upper and/or mid zones and spares the costophrenic angles. Nodules (2-5 mm), cysts (<10mm), and reticulation (a network of straight or curved lines) may be seen. There may be enlargement of the central pulmonary arteries. By HRCT, fine nodules, sometimes with small cavities, are present. They are often in the center of the lobule. Nodules may expand and become confluent . Some have irregular edges. Cysts, which are usually less than 1 cm in diameter, but may be up to 8 cm in diameter, are uniformly scattered both centrally and peripherally, and may occur alone or next to nodules [11,12]. Parenchyma between lesions appears normal . Based on CT scans, it has been suggested that nodules, cavities, and enlarging cysts develop sequentially . With progression, honeycombing, which spares the lower portions of the lungs, develops. Lung volumes are usually normal or increased even in the late, scarred stage . With remission of disease, nodules clear, but cystic spaces remain .
Summary of Radiographic Findings in LCH [11,12]
Radiographic differential diagnosis [11,12]
Lymphangioleiomyomatosis--cysts not associated with nodules
Cystic bronchiectasis--cysts related to segmental airways
Cystic mesenchymal hamartoma
Honeycombing of usual interstitial pneumonia--honeycomb forms a network involving lower lobes predominantly; lung volumes decreased
Histologic changes: At low power, stellate or rounded lesions (mm to cm in size), which frequently cavitate, usually occur around bronchioles. The lesions are predominantly interstitial, destroy bronchiolar wall structures, and narrow or occlude bronchiolar lumens and adjacent vessels, but a necrotizing angiitis does not occur. The lesions also destroy adjacent alveolar walls to produce emphysema. Several lesions may be present in one histologic section , but rarely, many sections must be searched to find a lesion . There may be a prominent DIP-like reaction in the surrounding alveoli . With time the cellular lesions undergo fibrosis, coalesce, and produce honeycombing in the upper or mid lung zones. Interestingly, both cellular and scarred lesions may be present in the same lung indicating that disease is progressive [3,14].
At high magnification, the individual LCs have normal nuclear/cytoplasmic ratios; pale, twisted, or indented nuclei; and pink cytoplasm with ill-defined cell borders. Mitoses may be frequent. Accompanying the histiocytes are eosinophils, which vary in number from very sparse to numerous; lymphocytes; and a few multinucleated giant cells. The eosinophils and giant cells account for the former terms eosinophilic granuloma and Langerhans' cell granulomatosis. Well-defined granulomas are absent in this disease. The LCs must be distinguished from alveolar macrophages, which have rounder nuclei and distinct cytoplasmic boundaries. The latter often have light brown smokers' pigment in their cytoplasm. These macrophages may be found within the Langerhans' nodules, as well as in the alveolar spaces .
Immunohistochemical staining of the Langerhans' cell: Histologic diagnosis used to be based on the H&E stain alone. It was confirmed by finding the pentalaminar Birbeck body (see below) by electron microscopy. More recently, the S-100 stain became useful to confirm a suspected diagnosis. Staining indicates LCH if it occurs in the interstitial aggregates of suspected LCs. However, S-100 also stains myoepithelial cells of bronchial glands, bronchial cartilage, and interdigitating reticulum cells in lymphoid aggregates, and positively stained cells are found in small numbers in a variety of interstitial lung diseases . Now, staining of paraffin sections with antibody to CD1a (OKT6), which is more specific for the LC, is the preferred diagnostic test. It stains the cell membranes . Still, it is necessary to confirm that the staining occurs in the cells with the typical indented nuclei.
Electron microscopy: Racquet- or rod-shaped, pentalaminar, Birbeck bodies--up to 1 µm long (33 nm diameter) and sometimes in continuity with the plasma membrane--are seen in the LCs [1,17]. High magnification is necessary to find these structures. Currently, there is no need to perform electron microscopy to make a diagnosis of LCH, as the histologic pattern along with a positive stain for CD1a is diagnostic. Surveys of various fibrosing and neoplastic lung diseases have shown that scattered LCs are present. These cells are not considered to be a manifestation of LCH [18, 19].
Clinical pathologic correlations: The destructive bronchiolar lesions account for the airway obstruction that may occur. Extension of the inflammation into blood vessel walls causes narrowing and produces the decreased diffusing capacity and hypertension that may occur. Extension of the cavitated nodules to the pleura predisposes to inflammatory destruction of the pleura and pneumothorax, especially when there is air trapping related to the bronchiolar narrowing.
Summary of Histologic Features
Histologic differential diagnosis 
Pathologic diagnosis: Open lung biopsy is the best procedure. Transbronchial biopsy has a low yield (2 of 12 in one series , 4 of 10 in another ). Examination of BAL fluid for LCs has its advocates. In one study, staining of BAL cells for CD1a showed some overlap in the percentages of cells from patients with LCH and those with other lung conditions . Another study found a range of 3-7% of LCs in LCH and up to 2% in controls . A third study found that controls had fewer than 3.6% CD1a+ cells and all 6 patients with LCH had 5-7% positive cells . It should be noted that smokers without LCH have more CD1a+ cells in lavage fluid than non-smokers . With these variations and the small numbers of patients examined, open lung biopsy is preferred for diagnosis until the ranges of values of CD1a+ cells in smokers, patients with other lung diseases, and patients with LCH are better established .
Pathogenesis: Cigarette smoking is thought to be a cause of pulmonary LCH, but no mechanism is known. Smoking has not been implicated in other variants of LCH. However, in all types of LCH examined to date, the proliferating cells appear to be clonal. Studies in women with the disease have shown a deviation from the expected ratio of a maternal and paternal X-linked gene--the HUMARA (human androgen receptor) gene. In women, this X-linked gene has a high frequency of polymorphism (most females have a different paternal and maternal allele) and the inactive X is consistently methylated. Compared to normal tissues, cells of LCH lesions showed a ratio of active to inactive alleles that was significantly different from 1, indicating clonality. Nevertheless, clonality does not necessarily signify neoplasia, as reactive clonal proliferations may occur .
A further pathogenetic factor may be an increased number of pulmonary neuroendocrine cells. In patients with LCH, these cells have been found to be increased ten fold over those in smokers without the disease. It is hypothesized that these cells produce bombesin-like peptides (which are chemotactic for monocytes and mitogenic for fibroblasts) that may be involved in the pathogenesis of the disease .
Finally, enzymes that destroy tissue matrix (matrix metalloproteinases) have been shown to be present in the LC of LCH. These proteinases may promote the escape of LC into alveolar spaces and the production emphysema that surrounds the lesions .
Association with cancer: In one series, 10 of 21 patients had one or more neoplasms (3 lung cancers, 1 lung carcinoid, 2 lymphomas, 5 extrapulmonary carcinomas, 1 mediastinal ganglioneuroma) before, coincident with, or after diagnosis of LCH. Cigarette smoking may be a common etiologic factor for the lung cancers . A possible association with Hodgkin's disease has also been described .
Treatment: Options include cessation of cigarette smoking, steroids for severe disease (although benefits are unknown), caution about pneumothorax with air travel or travel to high altitudes, and lung transplantation. Lung transplant has been successful in 5/7 cases with no extrapulmonary disease (patients well at 15, 30, 70, 80, and 90 mo post transplant). Two patients with extrapulmonary disease who resumed smoking had recurrences .
Prognosis: In most patients with LCH limited to the lung, the course is benign. Resolution or stabilization occurs. Median survival in one study was 13 y (range 1-29 y) . In this particular study, a large number (12/45 (27%)) died or underwent lung transplant . Poor prognosis was related to age >26 y, FEV1/FVC <0.66 and RV/TLC >0.33 . Long-term follow-up is rarely reported. One 25-year-old man had diffuse, fine, miliary radiographic changes and dyspnea in 1956. An open biopsy was interpreted as usual interstitial pneumonia. No therapy was given. In 1970, dyspnea, not responsive to prednisone, worsened. He died of cor pulmonale in 1981 at age 50. Review of the biopsy showed LCH, and autopsy showed non-specific honeycombing .
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Last revised 8/22/98
Copyright 1998 by Martha L. Warnock. All rights reserved.
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