From the Archives of the AFIP

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1 AFIP ARCHIVES 821 CME FEATURE See accompanying test at /education /rg_cme.html LEARNING OBJECTIVES FOR TEST 6 After reading this article and taking the test, the reader will be able to: Describe the evolution of the current understanding of pulmonary Langerhans cell histiocytosis. Discuss the clinical presentation of patients with pulmonary Langerhans cell histiocytosis. List the pathologic features of pulmonary Langerhans cell histiocytosis and address the difficulties and controversies related to its histologic diagnosis. Define the imaging features of pulmonary Langerhans cell histiocytosis. From the Archives of the AFIP Pulmonary Langerhans Cell Histiocytosis 1 Gerald F. Abbott, MD Melissa L. Rosado-de-Christenson, MD Teri J. Franks, MD Aletta Ann Frazier, MD Jeffrey R. Galvin, MD Pulmonary Langerhans cell histiocytosis (PLCH) is an isolated form of Langerhans cell histiocytosis that primarily affects cigarette smokers. PLCH is characterized by peribronchiolar proliferation of Langerhans cell infiltrates that form stellate nodules. The nodular lesions frequently cavitate and form thick- and thin-walled cysts, which are thought to represent enlarged airway lumina. PLCH lesions display temporal microscopic heterogeneity, with progression from dense cellular nodules to apparently cavitary nodules to increasing degrees of fibrosis that may extend along alveolar walls. In advanced cases, fibrotic scars are surrounded by enlarged, distorted air spaces. Affected patients are typically young adults who often present with cough and dyspnea. The characteristic radiographic features of PLCH are bilateral nodular and reticulonodular areas of opacity that predominantly involve the upper and middle lung zones with relative sparing of the lung bases. High-resolution computed tomography (CT) shows nodules and cysts in the same distribution and allows a confident prospective diagnosis of PLCH in the appropriate clinical setting. In typical cases, a predominantly nodular pattern is seen on CT scans in early phases of the disease, whereas a cystic pattern predominates in later phases. The radiologic abnormalities may regress, resolve completely, become stable, or progress to advanced cystic changes. Treatment consists of smoking cessation, but corticosteroid therapy may be useful in selected patients. Chemotherapeutic agents and lung transplantation may be offered to patients with advanced disease. The prognosis of PLCH is variable with frequent regression, stabilization, or recurrence of disease that does not correlate with cessation or continuation of smoking. Abbreviations: GM-CSF granulocyte-macrophage colony stimulating factor, H-E hematoxylin-eosin, LC Langerhans cell, LCH Langerhans cell histiocytosis, PLCH pulmonary Langerhans cell histiocytosis, TNF- tumor necrosis factor- Index terms: Histiocytosis, Lung, CT, Lung, diseases, ; 24: Published online /rg From the Department of Diagnostic Imaging, Brown Medical School, Rhode Island Hospital, 593 Eddy St, Providence, RI (G.F.A.); Department of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md (M.L.R.); Department of Diagnostic Radiology, University of Maryland Medical System, Baltimore (A.A.F., J.R.G.); and Departments of Pulmonary and Mediastinal Pathology (T.J.F.) and Radiologic Pathology (A.A.F., J.R.G.), Armed Forces Institute of Pathology, Washington, DC. Received January 9, 2004; revision requested January 23 and received February 10; accepted February 16. All authors have no financial relationships to disclose. Address correspondence to G.F.A. ( gabbott@cox.net). The opinions and assertions contained herein are the private views of the authors and are not to be construed as official nor as representing the views of the Uniformed Services University or the Department of Defense.

2 822 May-June 2004 RG f Volume 24 Number 3 Introduction Pulmonary Langerhans cell histiocytosis (PLCH) is a rare pulmonary disorder that typically affects young adults and is associated with cigarette smoking. The normal Langerhans cell (LC) is a dendritic cell that occurs in epithelial surfaces, particularly the skin, and was first described in A similar cell was later identified in patients with a variety of systemic disorders and focal or multifocal bone lesions characterized by infiltrates of LCs and other inflammatory cells. In the mid- 20th century, isolated pulmonary involvement by Langerhans cell histiocytosis (LCH) was first described. The advent of high-resolution computed tomography (CT) allowed imaging and characterization of these lesions in vivo, and three-dimensional reconstruction of serial histologic sections advanced the understanding of their morphology. This article describes the clinical, pathologic, and imaging features of PLCH. Background The LC was first described in 1868 by Paul Langerhans, a German medical student, during his study of tactile corpuscles in human skin. Using the Conheim gold chloride staining technique, Langerhans identified unique nonpigmented cells of dendritic morphology in the epidermis (1,2). Because this technique also stained neural elements, he initially thought that the LC represented an epidermal nerve receptor, but he later retracted his original proposal (3). For many years thereafter, LCs were thought to represent effete or worn-out melanocytes (1,4). In 1961, while studying the electron microscopic features of basal melanocytes and LCs in patients with vitiligo, Birbeck et al observed distinctive granules (Birbeck granules) in the cytoplasm of normal epidermal LCs, which to date remain specific markers for these cells (1,5). Almost 100 years after Langerhans original observations, LCs were linked to a heterogeneous group of disorders and clinical syndromes currently known as LCH (4). In 1941, Farber recognized histologic similarities in three different disorders known as Letterer- Siwe disease (a fulminant multiorgan histiocytosis of infants and children that affects the liver, spleen, lymph nodes, lungs, and bones), Hand- Schüller-Christian disease (a disseminated but chronic histiocytosis characterized by the triad of skeletal lesions, exophthalmus, and central diabetes insipidus), and eosinophilic granuloma (solitary or multiple histiocytosis of bone) (4 6). Farber postulated that these conditions represented differences in degree and site of involvement of the same basic disease (6). Although pulmonary involvement was recognized in some of these disorders, isolated pulmonary involvement was first reported in 1951 in two cases of eosinophilic granuloma of lung (7). In 1953, Lichtenstein grouped these three conditions under the term histiocytosis X or HX. The X descriptor referred to the unknown cause and pathogenesis of these diseases (8). In 1965, Basset et al described peculiar ultrastructural granules in the cytoplasm of large cells found in the lesions of a patient with pulmonary eosinophilic granuloma (4). They initially postulated that these granules represented viral inclusions, but the granules were subsequently also identified in the large histiocyte-like cells characteristic of histiocytosis X lesions and were provisionally called X bodies (4). The realization that these particles were in fact Birbeck granules led investigators to conclude that the LC was not related to melanocytes or nerve cells but was probably an immunologically important cell related to histiocytes or macrophages (1). In 1973, Nezelof et al postulated that histiocytosis X was a proliferative disorder of LC origin (4). For many years, multiple terms were used to refer to histiocytosis X and its related conditions, including eosinophilic granuloma, Letterer-Siwe disease, Hand-Schüller-Christian syndrome, Hashimoto Pritzker syndrome, self-healing histiocytosis, pure cutaneous histiocytosis, Langerhans cell granulomatosis, Langerhans cell (eosinophilic) granulomatosis, type II histiocytosis, and non-lipid reticuloendotheliosis (9). In 1987, the Histiocyte Society endorsed the term Langerhans cell histiocytosis to replace the term histiocytosis X (4). A decade later, they presented a consensus opinion to provide a practical categorization of these disorders that included views on histogenesis and aids to diagnosis (9). Patients with LCH were categorized as (a) those with single-system disease affecting a single site, (b) those with single-system disease affecting multiple sites, and (c) those with multisystem disease. In addition, isolated PLCH affecting adults was categorized as an LCH variant different from the severe and lethal pulmonary involvement seen in multisystem disease (9). In fact, it is now recognized that the majority of patients with pulmonary involvement by LCH have disease limited to the lung (10). Pathogenesis Langerhans Cell Histiocytosis Despite decades of study, the pathogenesis of LCH remains poorly understood. Several studies have shown that LCH lesions represent clonal cellular proliferations similar to those that characterize neoplastic disorders (8,11). However, it has also been argued that the clonal nature of the cells does not define LCH as a neoplasm and that clonal cells have been detected in disorders that may not be overtly malignant (8,12). Somatic

3 RG f Volume 24 Number 3 Abbott et al 823 mutations, viral infections, and immunologic factors have all been proposed as potential causes of the LC proliferations in LCH, but no definitive proof for any of these mechanisms has been provided. It has also been suggested that LCH cells represent a form of activated LCs, based on their expression of adhesion molecules. Immunologic dysregulation has also been proposed as a possible cause of LCH based on the production and presence of cytokines within LCH lesions, particularly granulocyte-macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor- (TNF- ) as well as several other cytokines (8). Pulmonary Langerhans Cell Histiocytosis The pathogenesis of PLCH also remains unknown and may be different from that of LCH (13). In fact, it has been demonstrated that most PLCH nodules are nonclonal and that the majority of the clonal nodules found are associated with a nonclonal LCH cell population (14). It has been suggested that PLCH is an uncontrolled immune response to an unknown exogenous antigen in which LCs may serve as accessory cells in the activation of T lymphocytes. The hypothesis is supported by the fact that the evolution of PLCH lesions is typical of an immune reaction. There is a predominance of LCs and lymphocytes in cellular lesions, progression to lesions with increasing numbers of inflammatory cells and fibrosis, and predominance of fibrosis with rare or absent LCs in end-stage lesions (15). There is a strong association between PLCH and cigarette smoking, and over 95% of affected patients in some series are cigarette smokers (16). Underlying host factors may also play a role, because only a small percentage of cigarette smokers develop PLCH (16). Although there are no direct experimental data that support the role of cigarette smoke in the pathogenesis of PLCH, the following observations suggest an etiologic link. 1. Although dendritic cells are widely distributed in normal lungs, LCs are almost exclusively located in the bronchial and bronchiolar epithelium. Cigarette smoking is associated with an increase in the number of dendritic cells and LCs in the lung and with a marked accumulation of LCs in the alveolar epithelium of normal smokers (17). LCs are also commonly recovered during bronchoalveolar lavage of patients with PLCH (18). 2. Cigarette smoke is known to induce the secretion of bombesin-like peptides by pulmonary neuroendocrine cells. These peptides may in turn promote secretion of cytokines by lung macrophages and stimulate fibroblasts with resultant lung fibrosis (19). 3. Tobacco glycoprotein is an immunostimulant that induces lymphocyte differentiation and lymphokine production. A known component of cigarette smoke, tobacco glycoprotein may play a role in the pathogenesis of PLCH by stimulating cytokine production (TNF-, GM-CSF) with resultant recruitment and activation of LCs (19). 4. Cigarette smoke itself may directly activate LCs to secrete cytokines such as TNF- and GM-CSF (19). 5. Antigens in cigarette smoke may be taken up by alveolar macrophages or LCs and may promote local expansion of T lymphocytes and local inflammation (19). 6. Tobacco glycoprotein is known to reduce lymphocyte proliferation and lymphocyte secretion of interleukin-2, which typically inhibits histiocyte proliferation. Thus, decreased levels of interleukin-2 may promote local proliferation of LCs in the lung (19). 7. Stressed or transformed epithelial cells may be the target for the immune response initiated by LCs. This hypothesis would explain the bronchiolar distribution of the disease, its occurrence in patients exposed to cigarette smoke (a common cause of bronchiolar hyperplasia), and its occurrence in nonsmokers who would develop bronchiolar abnormalities from exposures to other substances (17). PLCH has been described in association with malignant neoplasia, particularly bronchogenic carcinoma and Hodgkin lymphoma. PLCH may precede, occur concurrently, or follow the development of such neoplasms (20). In cases of bronchogenic carcinoma, the association may relate to the patient s history of cigarette smoking or the presence of pulmonary fibrosis (10). However, alterations in local cellular and humoral immune responses may play a role in an increased risk of bronchogenic carcinoma in patients with PLCH (21). Pulmonary irritants other than cigarette smoke may also result in an increased risk of PLCH, as there are reports of patients who develop PLCH following irradiation or chemotherapy for Hodgkin disease (17). Clinical Features PLCH is uncommon. In a clinical series of 502 patients, the diagnosis of PLCH was made in about 3.4% of individuals undergoing open-lung biopsy for chronic diffuse infiltrative lung disease (22). By comparison, the diagnosis of sarcoidosis was made in 12.5% of the same patient population. In another series, 15 cases of PLCH were reported, compared with 274 cases of sarcoidosis, over a 6-year period (10). However, the exact incidence and prevalence of PLCH is unknown because a significant number of affected patients may be asymptomatic and the disorder may undergo spontaneous resolution (19,22).

4 824 May-June 2004 RG f Volume 24 Number 3 Figure 1. LC morphology. Oil immersion photomicrograph (original magnification, 1200; hematoxylineosin [H-E] stain) shows LCs with irregular, deeply grooved nuclei and indistinct cell borders. PLCH typically affects young adults between the ages of 20 and 40 years, but it is reported to occur across a wide age range (1 69 years) (10). The gender distribution of PLCH is also variable. Some investigators report that men are more frequently affected than women (6,23,24), others report a female predominance (7,16,25), and still others report a roughly equal distribution of PLCH among men and women (19,26). PLCH is also reported to typically affect Caucasians (19). Most patients with PLCH are symptomatic, and the most frequent presenting complaints include nonproductive cough (50% 70% of cases) and dyspnea (35% 87%). Less common presenting symptoms include fatigue (16% 30%), weight loss (9% 30%), chest pain that is frequently pleuritic (9% 18%), and fever (15%) (7,16,25,27). Wheezing and hemoptysis are uncommon. Affected patients may also present with constitutional complaints, including nausea, vomiting, malaise, anorexia, and night sweats. The duration of symptoms before clinical presentation ranges from a few days (in the small percentage of patients who present because of a spontaneous pneumothorax) to 20 years. However, most patients report symptoms with durations of approximately 1 3 months before diagnosis (7,10,28). Approximately 25% of patients with PLCH are asymptomatic, and the disease is diagnosed because of incidentally discovered radiographic abnormalities (7,29). The majority of patients with PLCH are cigarette smokers, with a smoking prevalence that ranges from 80% to 100% in various studies (6,7,16,24,25). Although most patients with PLCH are heavy smokers, there is no evidence that degree and duration of smoking correlate with severity of disease (7,30). However, because most patients with PLCH are young, their cumulative smoking history may be modest (30). Results of physical examination may be entirely normal (62% of cases) or may include observations of diminished breath sounds, rales, or wheezing as isolated findings or in combination (7). Pneumothorax occurs in up to 25% of patients over the course of their disease and may be recurrent or bilateral (6,23 25,30). A very small number of patients may exhibit digital clubbing at presentation (10,30). Results of laboratory blood tests in patients with PLCH are generally within the limits of normal. Although eosinophils are often identified in microscopic analysis of PLCH lesions, patients exhibit no laboratory evidence of peripheral blood eosinophilia (16). The erythrocyte sedimentation rate may be moderately elevated (16,30). There is great variability of pulmonary function in patients with PLCH. Obstructive, restrictive, and mixed patterns have been described (30). The most common pulmonary function abnormality in patients with PLCH is reduced carbon monoxide diffusing capacity (DL CO ). It has been postulated that the prevalence of reduced diffusing capacity in patients with PLCH may reflect pulmonary capillary involvement and that associated pulmonary vascular dysfunction is likely related to the diminished exercise capacity of patients with PLCH (6,7,27). Vital capacity (VC) is frequently reduced, whereas residual volume (RV) is often normal or increased. As a consequence, the total lung capacity (TLC) is typically relatively normal (30). Decreased exercise tolerance is also a common presenting feature of pulmonary arterial hypertension, and in one study of 21 patients with end-stage PLCH, all developed pulmonary hypertension that was generally more severe than that encountered in other chronic lung diseases (31). Other functional abnormalities include reduction in the forced vital capacity (FVC) and a decrease in the ratio of forced expiratory volume in 1 second (FEV 1 )to forced vital capacity (27,26). Pathologic Features Background The term histiocyte may be used to designate cells of both monocyte-macrophage and dendritic cell LC lineage (9). Both cell lines are derived from CD34 bone marrow stem cells and form an integral part of the immune system (32,33). Dendritic cells and LCs are present in normal human lung tissue where they function as potent accessory or antigen-presenting cells responsible for the induction of primary antigen-specificimmune reactions (15,34,35). Antigen presentation is required before T-cell activation can begin, and results of in vivo studies suggest that dendritic cells LCs are times more efficient than

5 RG f Volume 24 Number 3 Abbott et al 825 Figure 2. Electron microscopic features of LCs. (a) Drawing of an LC shows numerous surface dendritic processes, a convoluted nucleus, and a prominent nucleolus. Rod-shaped Birbeck granules (inset) characteristically have a pentalaminar appearance with a zipperlike central axis. Dilatations at the rod ends give granules their characteristic tennis racquet appearance. (b) High-power electron photomicrograph demonstrates Birbeck granules located near the cell nucleus. Note parallel linear structures separated by finely granular material and a terminal expansion producing the tennis racquet appearance. Figure 3. Gross features of PLCH. Photograph of a lung biopsy specimen from a patient with PLCH demonstrates multiple grayish-white irregular nodules with intervening relatively normal lung parenchyma. cells of monocyte-macrophage lineage in stimulating lymphocyte activation (36,37). LCs are normally distributed in the skin, lymph nodes, bronchial mucosa, and thymus. Although morphologically and phenotypically similar to LCs, the cells in LCH lesions (ie, LCH cells) are functionally defective in antigen presentation. In addition, the distribution of LCH cells in bone, skin, lymph nodes, lung, liver, spleen, central nervous system, gastrointestinal tract, and bone marrow is rather different from the normal distribution of LCs (38). At light microscopy, LCs are of medium size (12 15 m) with pale pink cytoplasm, irregular deeply grooved nuclei, and small nucleoli (Fig 1). Cell borders are poorly defined because of numerous dendritic processes on the cell surface (Figs 1, 2). Electron microscopy reveals a unique cytoplasmic organelle the Langerhans or Birbeck granule that measures nm in length and nm in thickness. The rod-shaped granules have a pentalaminar appearance with a striated core situated between two electron-lucent layers and an electrondense limiting membrane (20). Dilatations can occur and, when present at the rod ends, give Birbeck granules their characteristic tennis racquet appearance (Fig 2). Phenotypically, LCs express surface CD1a glycoprotein and cytoplasmic S-100 protein, although the latter is not specific. Gross Features PLCH displays a spectrum of cellular and fibrotic lesions with variable cyst formation. As a result, the gross, histologic, and imaging appearances of PLCH lesions vary, since initial cellular infiltrates are progressively replaced by fibrous tissue. Tanwhite airway-centered nodules are distributed predominantly in the upper and middle lungs with either normal or fibrotic intervening pulmonary parenchyma. Individual nodules are well demarcated with irregular stellate borders. Although nodules may have central brown pigmentation or cyst formation, necrosis is absent in cystic areas. Nodules are typically less than 1 cm in diameter but may be as large as cm (Fig 3) (29).

6 826 May-June 2004 RG f Volume 24 Number 3 Microscopic Features At microscopic analysis, PLCH is characterized by discrete bronchiolocentric, stellate interstitial nodules separated by relatively normal or somewhat distorted lung tissue. Although PLCH lesions can be conceptualized as exhibiting early, intermediate, and late phases, temporal heterogeneity is typically present not only within a single biopsy sample but also within individual lesions. Early interstitial infiltration of bronchiole walls and epithelium by LCH cells is followed by fully developed nodules composed of LCH cells as well as variable numbers of lymphocytes, fibroblasts, eosinophils, neutrophils, plasma cells, and pigmented macrophages (Fig 4). The proportion of these cells varies enormously from case to case and from lesion to lesion in a given case. In particular, eosinophils may range from numerous (with formation of eosinophilic microabscesses) to rare or absent. Early cellular nodules are replaced in a centripetal fashion by a fibroblastic proliferation that results in the classic stellate lesions with central scarring and peripheral cellular tentacles that extend along alveolar walls (10). Eventually, the cellular infiltrates disappear entirely, leaving behind fibrotic scars surrounded by distorted and enlarged air spaces. These scars often retain the stellate shape of the cellular lesions. Pigmented (smoker s) macrophages, which are characterized by dusty yellow-brown cytoplasmic pigment, may fill adjacent air spaces, a feature referred to as a desquamative interstitial pneumonia like reaction (16). Cysts may develop in and around PLCH lesions and are thought to represent airway lumina that enlarge as a result of inflammation of the bronchiole wall, coalescence of adjacent affected airways, and paracicatricial air-space enlargement (39). Kambouchner and colleagues (40) used three-dimensional reconstructions of serial histologic sections to demonstrate that PLCH lesions are elongated, sheathlike structures of variable diameter that extend proximally and distally along bronchioles and do not necessarily have a spherical morphology (Fig 5). Diagnosis Because of its distinctive stellate appearance, the histologic diagnosis of PLCH is often apparent at Figure 4. Microscopic features of PLCH. Intermediate-power photomicrograph (original magnification, 480; H-E stain) of a nodular lesion shows infiltrates composed of variable numbers of LCH cells (arrow), eosinophils (arrowhead), lymphocytes, fibroblasts, plasma cells, neutrophils, and pigmented cells. The latter are smoker s macrophages derived from smoker s bronchiolitis. Figure 6. Scanning magnification appearance. Lowpower photomicrograph (original magnification, 12; H-E stain) of a wedge biopsy specimen shows discrete bronchiolocentric stellate lesions separated by uninvolved lung with air-space enlargement. scanning magnification (Fig 6). When characteristic lesions are present, examination of H-E stained lung biopsy specimens may be sufficient for diagnosis. However, in cases in which lesions are only suggestive rather than diagnostic, the findings from the H-E stained specimens should

7 RG f Volume 24 Number 3 Abbott et al 827 Figure 5. Three-dimensional appearance of a PLCH lesion. Artist s rendering, based on the reconstructions by Kambouchner et al (40), illustrates the elongated morphology and variable cellular and fibrotic composition of PLCH with correlative histologic sections. As a PLCH lesion evolves, the nodule of densely packed cells (bottom, a) is centripetally replaced by fibrous tissue and ultimately becomes a stellate scar (top, c). This continuum of change may be evident within a single lesion. PLCH lesions are bronchiolocentric and propagate both proximally and distally along the small airways. The involved bronchiolar lumen may become either dilated or obliterated. The histologic sections correspond to the early, middle, and late phases of PLCH. In the early phase (a), there is a densely cellular nodule with delicate stellate extensions along the adjacent alveolar walls (original magnification, 12; H-E stain). As the disease progresses (b), cellularity diminishes as fibroblasts replace the lesion (original magnification, 19.2; H-E stain). Note that the stellate extensions have become more prominent, the central bronchiole ( ) is dilated, and adjacent alveolar spaces have coalesced because of focal destruction of alveolar walls (paracicatricial airspace enlargement). In the final phase (c), the characteristic LCH cells are absent and only a fibrous, stellate scar remains (original magnification, 24; H-E stain). This phase is often accompanied by paracicatricial air-space enlargement ( ).

8 828 May-June 2004 RG f Volume 24 Number 3 be combined with proof that at least some lesional histiocytes possess the LC phenotype. The Birbeck granule is the most specific marker for this phenotype, and electron microscopy remains the standard for demonstration of this organelle. However, because of the expense and time required to process tissue, electron microscopy has largely been replaced by immunohistochemical analysis of formalin-fixed paraffin-embedded tissue. Detection of CD1a antigen in lesional cells by using conventional antibodies is sufficient for confirmation of the diagnosis (41). In the absence of demonstrable LCH cells, the presence of inactive stellate scars should provide a clue to diagnosis. Although not diagnostic, the presence of scars would support the diagnosis of PLCH when there are characteristic findings on high-resolution CT scans of the lung. Sampling error is a significant issue in the histologic diagnosis of PLCH because the lesions exhibit a multifocal and patchy distribution (10,42). Although the diagnosis can be established from transbronchial biopsy specimens in some cases, the diagnostic yield from this procedure is generally low (16,43). Most often, the histologic diagnosis of PLCH requires an open lung biopsy. Histologic Differential Diagnosis In general, the cellular lesions of PLCH are distinctive and there is no differential diagnosis (10). As described, inactive scars are not histologically specific, but their stellate shape and bronchiolocentric location should suggest the diagnosis. At light microscopy, the differential diagnosis of PLCH includes desquamative interstitial pneumonia, eosinophilic pneumonia, and usual interstitial pneumonia. PLCH is frequently misdiagnosed as desquamative interstitial pneumonia because the desquamative interstitial pneumonia like reaction associated with PLCH may be quite striking and obscure diagnostic lesions. However, desquamative interstitial pneumonia is a diffuse process that lacks the discrete bronchiolocentric, interstitial stellate nodules containing LCH cells that are seen in PLCH. In eosinophilic pneumonia, collections of eosinophils and macrophages fill alveolar spaces. This finding is typically accompanied by a mild interstitial pneumonia in which infiltrates of eosinophils, lymphocytes, and plasma cells expand alveolar walls. Eosinophilic pneumonia also lacks the discrete interstitial nodules and LCH cells associated with PLCH. Although fibrosis is a feature of both usual interstitial pneumonia and PLCH, the pattern of involvement is different. Usual interstitial pneumonia predominantly affects the posterolateral aspects of the lower lung zones, whereas PLCH involves the upper and middle lung zones. Microscopically, the fibrosis in usual interstitial pneumonia is subpleural or septal in distribution rather than bronchiolocentric as in PLCH (16). Imaging Features Radiography Most patients with PLCH exhibit chest radiographic abnormalities (23,26). Early in the disease, the most common radiographic manifestation is that of small nodules (Figs 7b, 8b), which typically range from 1 to 10 mm in diameter and are usually bilateral and symmetric in distribution (44). The nodules exhibit characteristic irregular borders, and the number of lesions visible on radiographs varies from three or four in each upper lung zone to innumerable or confluent nodules (7). The nodules are predominantly distributed in the upper and middle lung zones with sparing of the lung bases near the costophrenic sulci (Figs 7a, 8a) (7,44). The paucity of basilar lung lesions is most readily observed on frontal radiographs but is also apparent on most lateral views (7). A single study published in 1982 reported a middle and lower lung zone predominance of the radiographic abnormalities of PLCH (23).

9 RG f Volume 24 Number 3 Abbott et al 829 Figure 7. PLCH in a 41-year-old man with fatigue, malaise, weight loss, and a 50-pack year history of cigarette smoking. (a, b) Posteroanterior (a) and posteroanterior collimated (b) radiographs show subtle bilateral upper lobe nodules with indistinct borders. (c, d) High-resolution CT scans (lung window) of the right (c) and left (d) lungs show multifocal nodules and cysts. The nodules have irregular borders, and the cyst walls have variable thickness ranging from thin and uniform to nodular and irregular.

10 830 May-June 2004 RG f Volume 24 Number 3 Figure 8. PLCH in an 18-year-old woman with chronic cough and no known history of cigarette smoking. (a, b) Posteroanterior (a) and posteroanterior collimated (b) radiographs show subtle, bilateral reticular and nodular areas of opacity that predominantly affect the middle and upper lung zones and spare the lung bases. (c d) Targeted unenhanced high-resolution CT scans (lung window) of the upper (c), middle (d), and lower right (e) lung show irregular nodules as well as thin- and thick-walled cysts. The profusion of abnormalities is greatest in the upper lung and progressively decreases in the middle and lower lung zones.

11 RG f Volume 24 Number 3 Abbott et al 831 Figure 9. PLCH in a 35-year-old woman with a history of smoking who presented with a 3-month history of fever, chills, night sweats, weight loss, and nonproductive cough. Posteroanterior (a) and posteroanterior collimated (b) radiographs show bilateral coarse reticular areas of opacity and cystic changes that predominantly involve the upper and middle lung zones and spare the lung bases. Figure 10. PLCH in a 25-year-old woman with a 4-day history of increasing dyspnea. Posteroanterior radiograph shows bilateral pneumothoraces. Note reticular areas of opacity and cystic changes in the partially collapsed lungs. As the disease progresses, reticulonodular abnormalities may predominate (Fig 9) (44). Further progression may result in a predominance of cystic changes (Figs 9, 10). As cysts become more numerous, nodules tend to occur less frequently (19). The appearance of cysts in PLCH may mimic that of bullous emphysema or lymphangioleiomyomatosis, with multifocal contiguous cysts that measure up to 2 3 cm in diameter (19,44). End-stage PLCH is characterized by coarse reticular areas of opacity that tend to occur in the upper and middle lung zones and that may progress to honeycomb lung (44). Lung volumes are normal or increased in most patients with PLCH (Figs 7a, 8a, 9a) (7,26,45). However, decreased lung volumes are reported in a minority of affected patients (45). It has been postulated that the development of cystic lesions may counteract the fibrous retraction that occurs in end-stage PLCH (44). Pneumothorax is a recognized complication of PLCH (Fig 10). It may be the presenting manifestation of the disease and may recur (7,26,44). Interestingly, pneumothorax may occur in the absence of other radiographic pulmonary abnormalities (44). Pleural effusions occur infrequently but may be seen in association with pneumothorax or after diagnostic thoracotomy (23).

12 832 May-June 2004 RG f Volume 24 Number 3 Figure 11. PLCH in a 54-year-old woman with pleuritic chest pain. (a) Posteroanterior radiograph shows bilateral irregular nodular areas of opacity that predominantly affect the middle and upper lung zones and spare the lung bases. (b) Posteroanterior radiograph obtained 1 year later shows spontaneous regression and complete resolution of the radiographic abnormalities. Rare radiographic manifestations of PLCH include lymphadenopathy, air-space consolidations, solitary pulmonary nodule (47), and endobronchial mass with distal consolidation (44,46 48). Pulmonary artery prominence or enlargement has been described in cases complicated by pulmonary arterial hypertension (7,26,31). Different patterns of disease evolution may be recognized on chest radiographs. The radiographic abnormalities may regress or completely resolve (Fig 11), remain stable over several years, or progress to more prominent cystic changes (23). Chest radiography is limited in both its sensitivity and specificity for the detection and characterization of interstitial lung disease, and in some cases of PLCH, chest radiographs may appear normal. Subtle changes in lung lucency are often not detected. In addition, emphysema, cysts, reticulation, bronchiectasis, and cavitary nodules may mimic the radiographic findings of PLCH. Because most patients with PLCH are cigarette smokers, it may be difficult to distinguish emphysema from the lucent cysts of advanced PLCH (26). Computed Tomography CT, and especially high-resolution CT, are superior to radiography in demonstrating the morphology and distribution of lung abnormalities in patients with PLCH. High-resolution CT is most useful and sensitive for demonstrating the spectrum of imaging features of PLCH, and these findings reflect the macroscopic appearance of the disease (26,49,50). The distribution of high-resolution CT findings is usually apparent on axial images (Fig 8) but may be better depicted on coronal reformatted images (51). Grenier et al (45) compared the diagnostic values of chest radiography and high-resolution CT in the evaluation of patients with chronic diffuse interstitial lung disease. They found that highresolution CT is superior to radiography for making the diagnosis of PLCH. The high-resolution CT demonstration of cysts and nodules in a characteristic distribution allows a confident prospective diagnosis of PLCH (Figs 7, 8). When only cysts are present, the specificity of CT is limited, as other cystic lung diseases must be considered and excluded, but correlation with demographic and clinical factors may be helpful. The usefulness of high-resolution CT is enhanced by observer experience in interpretation of such scans in cases of diffuse interstitial lung disease (45).

13 RG f Volume 24 Number 3 Abbott et al 833 Figure 12. PLCH in a 31-year-old man with cough, anorexia, weight loss, and a 15 pack-year history of cigarette smoking. (a) High-resolution CT scan (lung window) shows nodules and thick- and thin-walled cysts. Some nodules exhibit a centrilobular distribution. (b) Low-power photomicrograph (original magnification, 12; H-E stain) demonstrates a cellular nodule with stellate peripheral extensions into adjacent alveolar walls. (c) Low-power photomicrograph (original magnification 30; H-E stain) shows one of the cystic lesions produced by bronchiolar dilatation. Note the surrounding paracicatricial air-space enlargement ( ). Brauner et al (52) described a predominantly nodular pattern as an early manifestation of PLCH on high-resolution CT scans, whereas a predominance of thin-walled cysts was typically seen in later phases of the disease. In most patients in their series, the main imaging feature was a combination of nodular and cystic lesions. Based on these findings, they postulated the following sequence of abnormalities seen on CT scans: nodules, cavitary nodules, thick-walled cysts, thin-walled cysts, and confluent cysts (52). The concept of progression of imaging abnormalities in PLCH was supported by the work of Soler et al (50). They correlated the cross-sectional imaging features of PLCH with the microscopic findings and showed that high-resolution CT can be useful in evaluating the histopathologic activity of the disease (50). In their series of 13 patients, a nodular pattern seen on high-resolution CT scans correlated well with florid granulomas, which likely represent the cellular peribronchiolar nodules described by Kambouchner et al (40). A cystic pattern did not have such a conclusive radiologic-pathologic correlation and represented either cavitary granulomas (likely corresponding to cellular lesions surrounding dilated bronchioles) or fibrous cystic lesions lacking LCs (Fig 12) (40,50). The authors also stressed that patients with a predominantly cystic pattern may be at risk for progression to severe respiratory failure and might require long-term follow-up (50).

14 834 May-June 2004 RG f Volume 24 Number 3 Figure 13. PLCH in a 54-year-old woman with a history of cigarette smoking, cough, and dyspnea. Unenhanced CT scans (lung window; a obtained at a higher level than b) show numerous bilateral irregular lung nodules, most numerous in the upper lung zones. Figure 14. PLCH in a 49-year-old woman with a history of cigarette smoking, increasing cough, and new onset of dyspnea. High-resolution CT scans (lung window) show bilateral irregular nodules and cysts predominantly distributed in the upper (a) and middle (b) lung zones with relative sparing of the lung bases (c). Note the irregular nodules that follow the course of an upper lobe bronchiole (arrow in a), an imaging feature that correlates with recent demonstrations of threedimensional morphology of the PLCH lesion (see Fig 5) (40). Nodules. CT excels in the demonstration of small nodules, a consistently underestimated feature of PLCH on chest radiographs (Figs 7c, 8d, 13) (26). High-resolution CT of nodular PLCH usually shows the typical middle and upper lung zone distribution of the nodules with relative sparing of the lung bases (Figs 8, 14, 15) (26,45, 52). The nodules may be few or innumerable and are typically surrounded by normal lung parenchyma (26,52). They typically measure 1 5mm in diameter but may be larger (Fig 12). Grenier et

15 RG f Volume 24 Number 3 Abbott et al 835 Figure 15. PLCH in a 30-year-old man with a history of cigarette smoking, recent fatigue, and malaise. The patient worked as a welder and sandblaster and was referred with a clinical and radiographic diagnosis of miliary tuberculosis. Highresolution CT scans (lung window) show irregular nodules and thick- (a) and thin-walled (b) cysts with relative sparing of the lung bases (c). Note the irregular morphology of some of the cystic lesions. al (45) evaluated 51 patients with PLCH by using high-resolution CT and observed nodules under 3 mm in diameter in 47% and nodules ranging from 3 mm to 1 cm in diameter in 45%. In 24% of those patients, the nodules exceeded 1 cm in diameter (45). The nodule margins are characteristically irregular (Figs 13, 15a), a feature that may be more apparent when cystic or fibrotic changes are present in the adjacent lung. Smooth nodule margins have also been described (44,52). High-resolution CT often shows a centrilobular, peribronchial, or peribronchiolar location of PLCH nodules (44,52), which may correlate with the bronchiolocentric orientation of the lesion as described by Kambouchner et al (Figs 12, 14, 15) (40). Most nodules are seen in association with cysts (Figs 7, 8, 12), but in rare instances, they are isolated findings (Fig 13) (52). The nodules of PLCH may be of homogeneous soft-tissue attenuation on high-resolution CT scans or may have central low attenuation (Fig 12). Nodular lesions typically exhibit regression on serial imaging studies (53).

16 836 May-June 2004 RG f Volume 24 Number 3 Figures 16, 17. (16) PLCH in a 34-year-old woman with cough, fatigue, and dyspnea. High-resolution CT scan (lung window) demonstrates a small right pneumothorax and bilateral irregular cysts, which vary in size and configuration. Some cysts appear to coalesce into larger, more irregular structures with bizarre shapes. (17) PLCH in a 47- year-old man with a history of smoking and worsening dyspnea. High-resolution CT scan (lung window) demonstrates predominantly thin-walled cysts of variable size and shape and a left pneumothorax. Cysts. Cystic lesions are the most common high-resolution CT feature of PLCH and usually measure less than 10 mm in diameter but may be as large as 20 mm (49). Cysts are often seen in association with nodules (Figs 7, 8, 12) but may be the only high-resolution CT finding (52). Reticular and reticulonodular areas of opacity seen on chest radiographs are uncommon on CT scans and probably represent cystic lesions (Fig 8) (26,44). The cysts occur predominantly in upper lung zones (Figs 8, 15) (54). Although they may manifest as round or ovoid cystic spaces, they may also exhibit bizarre configurations with bilobed, cloverleaf, and branching morphologies (Figs 16, 17). These appearances may result from coalescence of adjacent cysts or may reflect the peribronchiolar distribution of the PLCH lesion as depicted in Figure 5 (40,49). Cyst walls may be thin and barely perceptible (Fig 7d) or may appear thick and nodular on high-resolution CT scans (Fig 8c) (26,49,53). In the study by Grenier et al (45), thin-walled (wall thickness up to 2 mm) cysts were demonstrated in 88% of 51 patients with PLCH, whereas thick-walled ( 2 mm) cysts were seen in 53%. High-resolution CT performed at end expiration may show a reduction in the size of PLCH cysts compared with their size on inspiratory scans, a finding also seen in other cystic lung diseases (eg, lymphangioleiomyomatosis, cystic bronchiectasis, honeycomb lung, confluent centrilobular emphysema). This finding suggests communication between the cysts and the airways (55). The characteristic distribution of imaging abnormalities is unchanged in patients with advanced PLCH. Affected patients may exhibit CT evidence of fibrosis and honeycomb lung (44). Primack et al (54) evaluated 61 patients with endstage lung disease, eight of whom had PLCH. They were able to correctly diagnose all cases of end-stage PLCH, which were characterized by randomly distributed cystic spaces with well-defined walls and relative sparing of the lung bases (54). Imaging Differential Diagnosis The radiographic features of nodular PLCH are similar to those of other diseases that manifest as nodular areas of opacity (eg, sarcoidosis, silicosis, metastases, miliary tuberculosis, and other hematogenous infections) (44). The bilateral distribution of pulmonary nodules, predilection for the

17 RG f Volume 24 Number 3 Abbott et al 837 middle and upper lung zones, and relative sparing of the lung bases are highly suggestive of PLCH, particularly if the patient is a cigarette smoker. Correlation of radiographic findings with demographic factors, clinical presentation, and history of occupational or environmental exposures may be useful. Use of high-resolution CT markedly increases the diagnostic accuracy in cases of PLCH. When nodules are the only CT manifestation of PLCH, the differential diagnosis may include sarcoidosis, silicosis, tuberculosis, and metastatic carcinoma. The anatomic distribution of the nodules may be useful in narrowing the differential diagnosis. The nodules of PLCH typically follow a centrilobular distribution and thus differ from the nodules of sarcoidosis, silicosis, and lymphangitic carcinomatosis, which exhibit a perilymphatic distribution (49). The cystic changes of PLCH are readily distinguished from the cystic lesions of idiopathic pulmonary fibrosis, which are characterized by their subpleural and basilar distribution and their association with decreased lung volumes. Furthermore, PLCH cysts are typically surrounded by normal lung, whereas the honeycomb cysts of idiopathic pulmonary fibrosis are associated with adjacent lung parenchymal abnormalities such as ground-glass attenuation and architectural distortion. Predominantly cystic PLCH may mimic lymphangioleiomyomatosis, but the latter occurs almost exclusively in women and affects the lung diffusely. PLCH cysts may mimic the high-resolution CT findings of bronchiectasis but typically lack the branching features of this disorder. Cystic changes have also been described in emphysema, but in these cases the cystic areas represent foci of lung destruction that typically lack perceptible walls. Patients with Pneumocystis carinii pneumonia may develop lung cysts or pneumatoceles that may be indistinguishable from the cystic lesions of PLCH (49). Despite the above challenges in the high-resolution CT evaluation of patients with diffuse interstitial lung disease, a confident diagnosis of PLCH is often possible and was attained in 84% of cases in one study (56). The findings of cysts and nodules in the middle and upper lung zones with sparing of the lung bases are considered virtually diagnostic of PLCH (44). Therapy Cessation of smoking leads to stabilization of symptoms in the majority of patients with PLCH and may be the only intervention required (57). However, prospective studies to determine whether cessation of smoking influences the longterm progression of disease or its mortality have not been conducted (19). Although corticosteroid therapy has demonstrated beneficial effects in disease stabilization in some studies, there have been no randomized trials to compare the efficacy of this treatment with that of smoking cessation alone (19). Corticosteroids were reported to be beneficial in at least one case of pulmonary hypertension complicating PLCH (58). Patients with rapidly progressive PLCH have been treated with chemotherapeutic agents (eg, methotrexate, vinblastine, cyclophosphamide) without a significant therapeutic effect (6). Lung transplantation may be considered for patients with rapid deterioration of lung function. In these cases, smoking cessation is a prerequisite, since PLCH may recur in the transplanted lung if smoking is continued or resumed (59). Prognosis The clinical course of patients with PLCH is unpredictable. However, many patients have a good prognosis (44). Clinical and radiographic stabilization occurs in up to 50% of affected patients. Spontaneous regression is reported in up to 25% of patients (Figs 11, 18). In the remaining 25% of patients, PLCH follows a variably progressive, deteriorating course that culminates in diffuse cystic changes and lung destruction (49). Death may result from respiratory insufficiency or pulmonary hypertension, sometimes in combination (49). Vassallo et al (25) found that adult patients with PLCH have a shorter long-term survival compared with the general population and suffer substantial adverse effects on their health because of the disease. Basset and colleagues (6,19,44) identified six factors that demonstrated an association with an unfavorable prognosis: extremes of age, multiple pneumothoraces, extensive

18 838 May-June 2004 RG f Volume 24 Number 3 Figure 18. PLCH in a 52-year-old physician with a long history of cigarette smoking and worsening cough. (a c) High-resolution CT scans (lung window; obtained at cranial to caudal levels) at the time of diagnosis show nodules and cysts that predominantly affect the upper and middle lung zones. (d f) High-resolution CT scans (lung window; obtained at cranial to caudal levels) taken 3 years following cessation of smoking show marked improvement with near resolution of previously seen nodular and cystic lesions and evidence of centrilobular emphysema.

19 RG f Volume 24 Number 3 Abbott et al 839 multisystem disease, prolonged constitutional disturbance, extensive cysts or honeycombing on chest radiographs, and markedly decreased diffusing capacity. No definite association has been found between regression and relapse of PLCH and the continuation or cessation of smoking. Disease regression may occur whether or not a patient stops smoking (Fig 18) (28,60). Furthermore, PLCH may recur following radiologic regression of nodular lung abnormalities up to 7.5 years after the patient s initial presentation, and may do so in individuals who have stopped smoking (60). Adult patients with PLCH may be at increased risk for developing malignant neoplasms. Although a variety of neoplasms, including myeloproliferative disorders and lung cancer, have been associated with PLCH, the evidence regarding this association is inconclusive. Furthermore, the reported increased prevalence of lung cancer in adult patients with PLCH may be due to the high prevalence of cigarette smoking in that population. Although there is no conclusive evidence to link PLCH with the occurrence of lung cancer, a high degree of suspicion should be maintained, particularly in patients with PLCH who present with hemoptysis (19,61). Summary PLCH is a rare interstitial lung disease of unknown cause that primarily affects young adult cigarette smokers who typically present with cough, dyspnea, and mildly decreased diffusing capacity. The histologic diagnosis relies on the identification of LCs within peribronchiolar lesions that progress from densely cellular nodules of stellate morphology to increasingly fibrotic abnormalities, which may result in bronchiolar dilatation and paracicatricial air-space enlargement. The imaging features of PLCH include nodules and cysts that demonstrate a characteristic predilection for the upper lung zones and relative sparing of the lung bases. High-resolution CT findings may be diagnostic in the proper clinical setting. The prognosis is variable with frequent regression or stability of the abnormalities. Treatment is based on cessation of smoking, and corticosteroids may be effective in selected cases. Acknowledgments: We thank Deborah Desjardins for her immense assistance in the preparation of the manuscript. We also acknowledge the countless radiology residents who have participated throughout the years in the radiologic pathology courses of the Department of Radiologic Pathology of the Armed Forces Institute of Pathology in Washington, DC. Their case contributions enriched the content of the Institute s archives and enhanced our understanding of the radiologic-pathologic correlation of thoracic diseases. References 1. Rowden G. The Langerhans cell. Crit Rev Immunol 1981; 3: Pinkus GS, Lones MA, Matsumura F, Yamashiro S, Said JW, Pinkus JL. Langerhans cell histiocytosis: immunohistochemical expression of fascin, a dendritic cell marker. Am J Clin Pathol 2002; 118: Siegelman SS. Taking the X out of histiocytosis X. Radiology 1997; 204: Nezelof C, Basset F. Langerhans cell histiocytosis research: past, present, and future. Hematol Oncol Clin North Am 1998; 12: Lieberman PH, Jones CR, Steinman RM, et al. Langerhans cell (eosinophilic) granulomatosis: a clinicopathologic study encompassing 50 years. Am J Surg Pathol 1996; 20: Basset F, Corrin B, Spencer H, et al. Pulmonary histiocytosis X. Am Rev Respir Dis 1978; 118: Friedman PJ, Liebow AA, Sokoloff J. Eosinophilic granuloma of lung: clinical aspects of primary pulmonary histiocytosis in the adult. Medicine 1981; 60: de Graaf JH, Egeler RM. New insights into the pathogenesis of Langerhans cell histiocytosis. Curr Opin Pediatr 1997; 9: Favara BE, Feller AC, Pauli M, et al. Contemporary classification of histiocytic disorders: the WHO Committee on Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 1997; 29: Colby TV, Lombard C. Histiocytosis X in the lung. Hum Pathol 1983; 14: Willman CL, Busque L, Griffith BB, et al. Langerhans -cell histiocytosis (histiocytosis X): a clonal proliferative disease. N Engl J Med 1994; 331: Willman CL. Detection of clonal histiocytes in Langerhans cell histiocytosis: biology and clinical significance. Br J Cancer Suppl 1994; 23:S29 S33.