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Figure 1. Lung HRCT, initial stage. Presence of sporadic air cysts with thick wall, deployed previously at the superior lung fields. Pulmonary LCH Emanuela De Juli, M.D., Department of Pneumology, Niguarda Hospital, Milan, Italy Michaela Allen, M.D., Department of Pediatrics, IRCCS, Policlinico San Matteo, Pavia, Italy Maurizio Aricò, M.D., Onco Ematologia Pediatrica, Ospedale dei Bambini "G. Di Cristina", Palermo, Italy General overview of pulmonary LCH The form of Langerhans cell histiocytosis (LCH) best known as eosinophilic granuloma may present in adult patients as an exclusively pulmonary disease or as a multisystem disease with lung involvement as the main feature. Pulmonary LCH involves both the interstitial and the alveolar areas and shares all the clinical, physiopathological and radiological aspects of other interstitial lung diseases; in particular from a radiological point of view, it may be classified as a parenchymal abnormality of an air-cystic variety. LCH with isolated lung disease is relatively rare (3%) and according to the literature seems to be predominant in the Caucasian race, sporadic in blacks, and practically nonexistent in people of Asian origin. Risk Factors Although the etiology of LCH is still not fully understood, various reports of the literature suggest an association with some factors that may increase the risk of developing lung disease: Smoking: About 90-98% of patients with lung disease are cigarette smokers, although no particular correlation has been established between the total or daily consumption and the seriousness of the disease. Dusts/irritating agents: No cause-effect relationship has yet been demonstrated with professional exposure to dusts and irritating agents. Malignancies: Rare cases of LCH have been reported following Hodgkin disease treated with chemotherapy and radiotherapy. Pathogenesis The observance of Langerhans cell (LC) granulomas in the terminal bronchiolar wall suggests that an epithelial lesion in that site is the first step towards pulmonary LCH. Langerhans cells are normally present in the tracheobronchial epithelium, where their main function is to recognize inhaled agents. Their number increases when epithelium is damaged (i.e. by smoke) and in response to increased levels of granulocyte-macrophage colony-stimulating factor (GM-CSF). The information that most patients affected by LCH are smokers and have increased levels of GM-CSF suggests that alterations to the bronchial epithelium induced by smoking predispose towards the development of LCH by modifying the activity and the recruitment of Langerhans cells. The limit of this pathogenic theory is its discordance with the high percentage of smokers who do not develop LCH and the presence of histiocytosis in nonsmokers. It is likely that the pathogenesis of LCH is influenced by many factors and various mechanisms not yet fully understood or currently under study. Substances present in the cigarette smoke are under evaluation for their potential effect on LCH pathogenesis. Histology The typical lesions of pulmonary LCH are white nodules with indented margins and diameters ranging from 0.1 to 1.0 cm, sometimes hollow and associated with diffuse cystic alterations. Their center is occupied by Langerhans cells surrounded by lymphocytes, macrophages, eosinophils, fibroblasts, and some gigantic cells. These nodular lesions are preferentially found in the most distal bronchiolar districts. The morphologic aspect of the nodule varies, according to the stage of evolution of the disease, from transbronchial infiltration by Langerhans cells in the early phase, to fibroblast accumulation of the chronic lesions, to star-shaped scars surrounded by cystic areas in the end stage. The complete derangement of the lung parenchyma in the final stages and the focal nature of the pathological process make reaching a histological diagnosis difficult, and multiple biopsies are often necessary. DIAGNOSIS Clinical Manifestations PulmonaryLCH is certainly found more frequently in adults than in children. Around 36% of patients are not symptomatic at the time of diagnosis, while respiratory problems are reported in 70% of cases. The most common symptom is an insistent, dry cough (>50%), followed by dyspnea on exertion (>30%) and chest pain (20%). Spontaneous pneumothorax can be the first symptom of LCH and is certainly the main complication, occurring in about 10% of patients. Only very few patients complain of hemoptysis (6%) or wheezing (2%). As well as the respiratory symptoms, around 30% of patients with LCH may complain of tiredness and slight fever; 5% may present with polyuria and unquenched thirst due to diabetes insipidus, and others may present with aching bones. A physical examination rarely shows specific signs to indicate LCH. Furthermore, chest examinations in the majority of patients in the early stages of the disease are negative, unless pneumothorax is present. In later stages, peripheral cyanosis and tachypnea may appear and less frequently, clubbing of the fingers. The chest will present diminished expansion and vesicular breath. Patients with advanced pulmonary LCH may develop chronic "cor pulmonale" with pulmonary hypertension, which could explain a loud second heart sound and any signs of right ventricular failure. Radiologic Imaging of the Lung The elementary radiographic lesions that characterize LCH are primarily represented by air cysts and secondarily by interstitial nodular opacities, which are not always present. Chest Radiograph The radiological signs of pulmonary LCH are closely related to anatomicopathological lesions. In the early stages, bilateral opacities may be found, usually near the hilum. The most commonly seen radiological aspects are those of the granulomatous phase. These are nodular images, sometimes associated with reticular-nodular opacities that typically do not involve the costodiaphragmatic recess or the most distant basal regions. The radiological picture also allows for the presence of small air-cystic lesions that, in the early stages, are normally isolated and peripheral. These images gradually evolve in gross band opacities, alternating voluminous air cysts which are predominant in the apical segments. Other rare findings that are worth mentioning, as they have been reported in the literature, are mediastinal adenopathy accompanying the initial and granulomatous phase, pleural effusion, air-fluid levels in the cysts, and the exceptional finding of an endotracheal mass. CT of the Chest

High-resolution computed tomography (HRCT) is undoubtedly the best means we have for studying the vascular and bronchial tree, as it shows in detail the lobular organization of the lung parenchyma up to diameters of 0.5 mm. Compared to standard CT, which remains the ideal instrument for assessing vascular structures or tissues provided with enhancement, the high-resolution technique allows more accurate morphologic analysis of the pulmonary interstices by reducing the thickness of the tomographic "slices" to 1-2 mm.

Thus, chest HRCT is capable of identifying all the anatomical lesions of LCH, from the earliest to the latest, and at the same time allowing the extension in the pulmonary parenchyma to be evaluated.

The most common HRCT images seen in pulmonary LCH are:

• Thick-walled air cysts
• Micronodules and, more rarely,
• Ground-glass opacities
• Interstitial thickening

Air Cysts

These follow a longitudinal rather than an axial distribution pattern, are larger and more concentrated in the upper lobes, and are smaller and fewer in the middle lobes. Characteristically they leave the costodiaphragmatic recess untouched. The size of the cysts varies from a few mm to 3 cm in diameter, although cases have been reported of LCH with cysts reaching 5 cm in diameter and air-fluid levels within. The cysts are usually rounded in shape, unless they result from single coalescing cysts. This is the case in advanced and extensive LCH, in which large, well-delineated but gradually less segmented air spaces are formed.

Micronodules

These opacities are nodules of miliary size (0.5-4 mm) with undefined margins, sometimes hollow centers, and bronchiolocentric localization. The distribution pattern shows that they are generally not found in the diaphragm region or on the pleural surface, whereas they are present axially, both centrally and peripherally. These findings help to distinguish pulmonary LCH from other nodular interstitial diseases.

The hollow micronodular lesions may evolve by insufflation in thick-walled cysts or alternatively enlarge, forming well-defined nodules with a low tendency to merge.

Interstitial Thickening

Finally the tomographic picture of LCH may include alterations of the subpleural connective tissue that appears thickened with irregular and indented margins. The sectional thickening of the most peripheral lobules adjacent to the pleura may determine characteristic indentations of the visceral pleural profile by traction on the tightly related subpleural tissue.

These alterations are present both in the mantle area and in the mediastinal side and should be searched for, especially at an interlobar level.

Radiologic Differential Diagnosis

In radiologic terminology, the "air cyst" is a general expression which refers to any well-delineated air-filled space. The term may be used to describe any recognizable hypertransparent image of uniform wall thickness (1-3 mm).

The main radiologic lung alterations that present as air cysts are:

• "Honeycomb lung," which typically results from fibrosis of the peripheral parenchyma;
• Cystic bronchiectasis, caused by chronic infections (Aspergillus, bacteria, or MAC) or by deficient defense mechanisms (mucociliary clearance alteration, IgA deficiency, etc);
• Bullae, which may develop in emphysema, as well as in some viral or other infections (Pneumocystis carinii);
• Blebs, which may form on the surface of the visceral pleurae; and
• Cavities, localized within a consolidation process, a mass or a nodule.

On the other hand, the interstitial nodular images typical of LCH must be distinguished from nodules formed by blocked-up alveoli. This is not easy to do, but generally the LCH interstitial nodule has well-defined margins, does not tend to coalesce, and varies in size between a few mm and 1 cm.

Tests of Respiratory Function

Alterations of the respiratory function, identifiable in LCH patients, are extremely variable. Restrictive defects may be found in the initial phases of the disease, whereas evidence of obstructive or mixed respiratory dysfunction syndromes is characteristic of the more advanced stages, where air-cystic lesions are prevalent. However, in 10-15% of patients, we may find normal lung volumes, despite the presence of radiological alterations. The tests that may be carried out are:

• DLCO, which is reduced in 70-90% of cases, reflecting the defective gas exchange and the ventilation-perfusion mismatch.
• Lung volumes. The vital capacity (VC) is often significantly decreased, as compared to the residual volume (RV), so that the RV/TLC (residual volume/total lung capacity) ratio is increased in more than 2/3 of the patients. This may be due to the diffusion of the air-cystic lesions. The flow-volume chart describes a concave curve, probably expressing the peribronchial distribution of the lesions, causing obstruction and compression of the small airways. A clear decrease in the expiratory flow and a reduction in the FEV₁/FVC ratio are both signs of advanced lung LCH.
• Blood gas analysis, which may show pH values within the normal range and a more-or-less-marked hypoxemia, in accordance with the evolution of the pathologic process. A severe desaturation may be found during exertion.
• Spirometry. The spirometric tests do not always reflect the degree of radiological alteration. There have been cases of severe radiological alterations with no impairment of the respiratory tests, while significant spirometric dysfunction, accompanied by nonrelevant radiological images, is also possible. This is especially true in the initial phases of the disease, when a standard x-ray is not sensitive enough to show cystic lesions, whereas in the more advanced phases of LCH, radiographic and spirometric parameters are usually related.

Fiberbronchoscopy

An endoscopy of the entire tracheobronchial system of patients with pulmonary LCH does not normally reveal any kind of lesion. Likewise, a biopsy of the bronchial mucous membrane does not give any relevant information and should only be considered when differential diagnosis is needed.

Transbronchial biopsy (TBB) is more helpful for diagnostic purposes, although the percentage of positive results reported in the literature for this type of test is rather limited. It is likely that histological results are greatly influenced by the fact that typical LCH lesions do not spread uniformly or simultaneously in the lung parenchyma. This means that, for diagnostic purposes, it is essential to know the exact location of those areas affected by active lesions. Therefore, the ideal moment for a TBB, rather than the end stage, is during the florid phase of the disease, when there is an abundance of Langerhans cells and eosinophilic elements to be found.

As diffuse air cysts increase the risk of iatrogenic pneumothorax, HRCT images are therefore essential for guiding the biopsy. A valid diagnostic contribution is also given by the bronchoalveolar lavage fluid (BAL). Alterations found in the differential cell count in pulmonary LCH are:

• A total cell count above 106/ml with a prevalence of alveolar macrophages. Macrophagic alveolitis is a common finding in LCH patients with smoking habits, while it is usually missing in the small quota of nonsmoking patients.
• An increase in neutrophils with higher values than those found in "healthy" smokers.
• Modest eosinophilia.
• Langerhans cells. Their identification is carried out both by ultrastructural analysis and by immunohistochemical methods using anti-CD1a antibodies. The demonstration of Birbeck granules by electron microscopy is a specific finding.

Of the above, the first three are nonspecific to LCH. Furthermore, finding Langerhans cells in a BAL fluid may not be uncommon, and although it represents an important finding, it is difficult to establish a cutoff value, above which the diagnosis of LCH can be said to be accurate. A low quota of CD1a, in some cases reaching 3%, may be found in healthy smokers, whereas values of about 4% have also been reported in other interstitial lung diseases. Percentages higher than 5% have only been observed in patients with pulmonary LCH, which means that a value of 5% should therefore be considered the real cutoff point for a diagnosis of LCH. Nevertheless, the majority of LCH patients do not have such high values of Langerhans cells in the BAL fluid.

Lung Biopsy

In patients with nodular lesions whose HRCT images show few air cysts, if other interstitial lung diseases cannot be ruled out, most authors suggest proceeding to a surgical lung biopsy. This diagnostic approach is generally preferred to TBB, because of the higher number of positive results, thanks to the possibility of obtaining larger amounts of parenchymal tissue. When tomographic images strongly indicate the presence of LCH, the diagnostic benefit of proceeding with an open biopsy should be evaluated against the surgical risk.

Conclusions

Although much has been written from Lichtenstein onwards on the risk factors, diagnosis and prognosis of the disease, to this day LCH with its polyhedric nature, remains difficult to understand and is probably underestimated.

HRCT is an undoubtedly important means of diagnosing pulmonary LCH and of assessing the state and evolution of lung damage. We have seen how HRCT is fundamental for searching for typical primary lesions, as well as secondary signs, which are precious radiographic elements for studying the various phases of the disease and its possible complications. The literature also demonstrates that pulmonary LCH is not always confined to the lung and therefore, as in other cases of LCH, it is essential to look for other affected organs that may confirm the pulmonary radiological diagnosis without making use of more invasive procedures, especially in those patients with highly impaired respiratory function.

Our invitation to all clinicians treating pulmonary LCH is to widen their approach beyond an assessment of the lung, by taking into account the many forms in which LCH may present itself.