© 2002 American Thoracic Society
Pulmonary Langerhans Cell HistiocytosisWhat Was the Question?Mayo Clinic Rochester, Minnesota Pulmonary Langerhans cell histiocytosis (LCH) has been with us for over fifty years. In 1951 Farinacci and colleagues reported two adult patients with "eosinophilic granuloma" of the lungs (1). Six years later, Auld detailed microscopic characteristics of LCH in lung biopsies from five patients and in the process laid the foundation for all subsequent histopathologic studies of this condition (2). In nearly five decades since his careful and elegant description surprisingly little has been added to our understanding of the basic microscopic features of LCH. In this issue of AJRCCM, Dr. Kambouchner and coworkers (pp. 1483–1490) (3) report morphologic observations first published in preliminary form a decade ago (4). The authors studied serial histologic sections of 36 lesions captured in 12 surgical specimens from seven patients to address what they characterize as important, unresolved questions regarding LCH. The answers come as no surprise. To what extent are the lesions of LCH bronchiolocentric? The answer to this question is well established. As early as 1955 the relationship between the cystic spaces of LCH and bronchioles was noted in a case report (5). The authors of this early report also described residual bronchiolar epithelium in cyst walls, speculating on some of the mechanisms responsible for cyst formation. Two years later, Auld described and illustrated communication of "granulomatous masses" with bronchioles (2). Nearly all subsequent histopathologic studies have reiterated the consistent relationship between the nodules of LCH and distal airways (6–8). Kambouchner and colleagues demonstrate in greater detail that LCH affects predominantly respiratory bronchioles and to a lesser extent distal terminal bronchioles. They speculate that the lesions, centered on airway lumens, propagate in a continuous fashion proximally and distally with the potential to involve daughter bronchioles to the level of alveolar ducts. As such, the lesions are more linear than spherical. LCH can involve entire acinar units by tracking along multiple generations of respiratory bronchioles and alveolar ducts, thus forming macroscopically visible irregularly shaped nodules. The consistently bronchiolocentric distribution of LCH provides a teleological link to cigarette smoking, an association first noted in 1981 (6). A variety of research tools, applied to both human and animal tissues, hint at some of the cellular and molecular mechanisms that likely participate in translating cigarette smoke to non-neoplastic expansion of peribronchiolar Langerhans cells, the earliest lesion in the minor subset of smokers affected by this condition (9, 10). What is the three-dimensional appearance of LCH? Kambouchner and colleagues paint a three-dimensional picture of LCH using serial sections from a single "representative" nodule. The lesions of LCH are heterogeneous, as noted in this and other reports, and in that sense a single nodule cannot be truly representative. Nonetheless, the authors are successful in combining serial microscopic sections with a 3-D computerized reconstruction tool to offer the first artistic rendition of LCH in three dimensions. The computer-generated image is to conventional pathology what sculpture is to photography, and as such is beautiful to behold but comes as no surprise to those familiar with two-dimensional representations of LCH. What is the relationship between lesions of apparently different age within a single biopsy? As noted in the majority of previously published cases (6–8), all specimens examined in the current study demonstrated the full range of cellular "granulomatous" nodules and cystic fibrotic scars separated by relatively normal lung. To some extent this result was preordained by the decision to exclude cases in which only large, coalescent granulomatous lesions or fibrotic scars were present. Temporal heterogeneity was documented within individual lesions as they were tracked along bronchioles, indicating that each nodule recapitulates disease evolution from a cellular process to a fibrotic scar. Maturational heterogeneity within individual lesions of LCH is not a new observation, but we can now more clearly envision the orderly and linear progression from early infiltration of bronchiole walls and epithelium by Langerhans cells to fully developed cellular lesions followed by fibrosis and ultimately end-stage scarring. What mechanisms are responsible for cavitation and cyst formation? The cystic nature of LCH is a cardinal feature that characterizes its radiographic, gross, and microscopic appearance (11). Cystic change typically evolves in the wake of fibrosis by mechanisms not fully understood, although recent studies provide insights into some of the molecular and ultrastructural underpinnings (12–14). Kambouchner and coworkers demonstrate that cavities within nodules represent airway lumens that enlarge as a result of inflammation and fibrosis of bronchiole walls, coalescence of adjacent affected airways, and "traction emphysema" in peribronchiolar alveolar spaces. Traction emphysema, also termed "paracicatricial airspace enlargement," receives surprisingly little attention as the current investigators attribute the majority of cystic spaces to fibrous walled ectatic airway lumens. To a large extent they confirm previous conclusions regarding what some of the cystic spaces are, but provide little new information regarding basic mechanisms responsible for transforming cellular infiltrates into burned out cystic scars. In the final analysis the observations of Kambouchner and colleagues do not significantly expand our fund of knowledge regarding morphology and pathogenesis of LCH, but instead offer authoritative support for previously established tenets. The consistently bronchiolocentric distribution, irregular configuration, heterogeneous composition, and cystic nature of diagnostic lesions are features that have been emphasized by numerous investigators using essentially the same tools over the last five decades of scientific discovery. The orderly and linear relationship of these features is more fully established as a consequence of their efforts. But in providing more authoritative and detailed answers, we are left with a question: Is it more proper to consider LCH a form of bronchiolitis rather than an interstitial lung disorder? In fact, it may be both. The interstitium of the lung comprises all of its solid components and as such is not limited to the distal components of the pulmonary acinus. Lesions like LCH that reside chiefly within peribronchiolar interstitium can cause clinical, physiologic, and radiographic syndromes indistinguishable from many of the conditions traditionally sheltered under the generic and admittedly imprecise umbrella of diffuse interstitial lung disease. It is, in the end, a rose whether viewed in two dimensions or three. REFERENCES
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