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Extraosseous Langerhans Cell Histiocytosis in Children¹

¹ From the Department of Diagnostic and Interventional Radiology (S.S., L.A.M., F.G.) and Department of Pathology (I.L.), Centre Hospitalier Universitaire Vaudois-CHUV, Rue du Bugnon, 1011 Lausanne, Switzerland; Department of Pediatric Radiology, Kinderspital, Aarau, Switzerland (G.E.); Fondation Lenval, Hôpital pour Enfants, Nice, France (A.G.); Department of Pediatric Radiology, Hôpital Cantonal, Geneva, Switzerland (S.H.); Department of Pediatric Radiology, Kinderspital, St. Gallen, Switzerland (P.W.); and Department of Pediatric Radiology, Inselspital, Bern, Switzerland (R.W.). Presented as an education exhibit at the 2006 RSNA Annual Meeting. Received May 10, 2007; revision requested July 12; revision received and accepted August 27. All authors have no financial relationships to disclose. Address correspondence to S.S. (e-mail: sabine.schmidt{at}chuv.ch).

	Abstract

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Etiology and General Histologic... Imaging Features Summary References

 
Langerhans cell histiocytosis, a rare disease that occurs mainly in children, may produce a broad range of manifestations, from a single osseous lesion to multiple lesions involving more than one organ or system. The clinical course varies widely in relation to the patient’s age. Multisystem disease may demonstrate especially aggressive behavior in very young children, with the outcome depending largely on the stage of disease and the degree of related organ dysfunction at the time of diagnosis. Extraosseous manifestations are less commonly seen than osseous ones and may be more difficult to identify. To accurately detect extraosseous Langerhans cell histiocytosis at an early stage, radiologists must recognize the significance of individual clinical and laboratory findings as well as the relevance of imaging features for the differential diagnosis. The pattern and severity of pulmonary, thymic, hepatobiliary, splenic, gastrointestinal, neurologic, mucocutaneous, soft-tissue (head and neck), and salivary involvement in Langerhans cell histiocytosis generally are well depicted with conventional radiography, ultrasonography, computed tomography, and magnetic resonance imaging. However, the imaging features are not pathognomonic, and a biopsy usually is necessary to establish a definitive diagnosis.

© RSNA, 2008

	LEARNING OBJECTIVES FOR TEST 1

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Etiology and General Histologic... Imaging Features Summary References

 
After reading this article and taking the test, the reader will be able to:

• Describe the most likely pathogenetic mechanism in Langerhans cell histiocytosis.
  
• Recognize radiologic features that are suggestive of Langerhans cell histiocytosis in common extraosseous sites.
  
• Formulate appropriate differential diagnoses for Langerhans cell histiocytosis in each of the common extraosseous sites.
  

	Introduction

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Etiology and General Histologic... Imaging Features Summary References

 
The annual incidence of Langerhans cell histiocytosis is reported to be between 2.6 and 5.4 cases per million children in the general population. The peak age at initial diagnosis is from 1 to 3 years, but the disease may manifest at any age (1–5). Boys are more often affected than girls (1,6,7).

The most common manifestations of the disease are bone lesions, whereas extraosseous involvement is less frequently seen. Among a group of 31 children with extraosseous disease, we observed the following pattern of organ involvement, in order of decreasing frequency: skin (55%), central nervous system (35%), hepatobiliary system and spleen (32%), lungs (26%), lymph nodes (26%), soft tissues (26%), bone marrow (19%), salivary glands (6%), and digestive tract (6%) (8).

The disorder was first described on the basis of purely clinical observations more than a century ago, after the Langerhans cell was detected by the student Paul Langerhans in 1865 (1). Over the years, the terms eosinophilic granuloma, Hand-Schuller-Christian disease, and Letterer-Siwe disease were devised to denote the most common clinical manifestations within a broad spectrum of divergent disease patterns (from localized to multifocal involvement) with increasing degrees of severity. In 1953, Liechtenstein observed that the underlying component of all these manifestations was the histiocyte. This observation was followed by the recognition of the many separately defined syndromes as a single disease entity: histiocytosis X (X being the unknown etiologic factor) (1). In 1985, the Writing Group of the Histiocyte Society established a histiocytosis classification system based on distinct pathologic criteria and on the clinical evolution of disease. Under the definitive name Langerhans cell histiocytosis, the disease was designated as class I of the histiocytic disorders (9) (Table 1).

The radiographic skeletal survey is the cornerstone of the initial imaging evaluation for Langerhans cell histiocytosis because it allows the detection of bone lesions, which occur in most children affected by the disease (2,4,5,10,14). The radiographic features of osseous involvement have been reported extensively (7,14,15). By contrast, the widely varied features of extraosseous involvement, which are detectable only with the use of imaging modalities such as ultrasonography (US), computed tomography (CT), and magnetic resonance (MR) imaging, have been described less extensively. The published descriptions have been mostly anecdotal, appearing in case reports (16–21) or articles focused on findings in a single organ (22–26).

The present article provides an overview of the diverse radiologic manifestations of extraosseous Langerhans cell histiocytosis that may be observed with multimodality imaging, which allows exact depiction of the extent and severity of disease. Other entities that may produce radiologic features similar to those of extraosseous Langerhans cell histiocytosis and that are therefore commonly included in the differential diagnoses also are described.

	Etiology and General Histologic Features

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Etiology and General Histologic... Imaging Features Summary References

 
Little is yet known about the etiology and pathogenesis of Langerhans cell histiocytosis (12), despite the steady accrual of epidemiologic data (2,4,5,7). There is no evidence that the disease originates in a malignant neoplastic process (9,27), and no underlying viral or genetic cause has been identified. To date, the most likely theory postulates a histopathologically benign, primarily reactive, and probably immunologically mediated process similar to that in sarcoidosis (2,6,28,29).

The X in the older term histiocytosis X reflects the earlier lack of understanding of the disease etiology and the underlying pathophysiologic process, whereas the current term Langerhans cell histiocytosis reflects the more recent recognition of the central role of the Langerhans cell in the disorder, as well as the definition of specific morphologic, immunohistochemical, and clinical criteria for diagnosis (6,29). Langerhans cells are highly differentiated histiocytes of the stellate dendritic antigen-presenting cell lineage. First recognized as a component of the normal human skin by Paul Langerhans in 1865 (30), they originally derive from bone marrow. The importance of their immunologic role is now recognized: They are able to detect foreign antigens entering the body through the skin and then to migrate from the skin to the lymph nodes (31,32).

The hallmark of Langerhans cell histiocytosis is an uncontrolled monoclonal proliferation of abnormal Langerhans cells, which may infiltrate nearly any tissue or organ as well as lymph nodes. This histiocytic infiltration is accompanied by chronic inflammation and the formation of granulomas. The process most likely reflects an uncontrolled immune response triggered by an as yet unknown antigen (27).

The diagnosis of Langerhans cell histiocytosis is based on the results of biopsy. The histopathologic features are remarkably similar, regardless of the site of the lesion (Fig 1). Electron microscopy, the standard of reference, depicts Birbeck bodies within the cellular cytoplasm. Originally described by Birbeck in 1961, these structures today are considered unique to Langerhans cells (2,28,33). Birbeck bodies are rigid tubular structures of variable length that characteristically possess a striated or zipperlike central core (Fig 2). They may originate as invaginations of the cell membrane (2).

View larger version (151K): [in this window] [in a new window] [Download PPT slide]   Figure 1.  Photomicrograph (original magnification, x400; hematoxylin-eosin stain) shows a proliferation of Langerhans cells (straight arrows), which are characterized by a moderate amount of eosinophilic cytoplasm, elongated kidney-shaped nuclei, and a nuclear groove (curved arrows). The Langerhans cells are associated with macrophages, lymphocytes, and numerous eosinophils (arrowheads).

View larger version (218K): [in this window] [in a new window] [Download PPT slide]   Figure 2.  Electron photomicrograph (original magnification, x46,000) shows Birbeck bodies within the cytoplasm of a Langerhans cell. Note the zipperlike central core and the bulbous structure at one end of each Birbeck body, features that cause it to resemble a tennis racket (arrows).

The second most specific test is immunohistochemical staining to determine whether CD1a glycoprotein antigen is present on the cellular surface, another criterion for the diagnosis of Langerhans cell histiocytosis (9,27) (Fig 3). However, CD1a positivity also may occasionally be seen in other histiocytoses, such as juvenile xanthogranuloma and Rosai-Dorfman disease (28).

View larger version (153K): [in this window] [in a new window] [Download PPT slide]   Figure 3.  Photomicrograph (original magnification, x400) obtained at immunohistochemical analysis after staining with antibodies to CD1a, a glycoprotein antigen at the cellular surface, shows abundant Langerhans cells (brown-stained areas).

Finally, the presence of S100 protein remains a useful indicator of histiocytic disorders, although it is not diagnostically specific. A positive result of staining for S100 indicates the likelihood that lesional histiocytes are Langerhans cells, indeterminate cells, or interdigitating dendritic cells. However, additional positive findings at electron microscopy, staining for CD1a, or both are necessary for verification of a positive S100 test result (28).

	Imaging Features

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Pulmonary Involvement
Pulmonary lesions have been found in fewer than 10% of children with a solitary site of involvement in Langerhans cell histiocytosis but in 23%–50% of those with multisystem involvement (8,26,34–36). The established diagnostic procedures are lung biopsy and bronchoalveolar lavage with a score of more than 5% CD1a-positive cells (37).

At histopathologic analysis, pulmonary involvement in Langerhans cell histiocytosis is characterized by the rapid proliferation of Langerhans cells almost exclusively in the bronchial and bronchiolar epithelium. This cellular proliferation occurs as an uncontrolled immune response to an unknown stimulus, and it leads to the formation of destructive granulomas adjacent to the small airways. Cavitation of these granulomatous nodules subsequently occurs, leading to air trapping, airway obstruction, and, finally, the formation of often bizarrely shaped cystic lesions with varied wall thicknesseses and sizes (38).

Initial chest radiographs show diffuse, bilateral, symmetric interstitial disease with a characteristic reticulonodular pattern that results from the summation of nodules and thin cystic walls (Fig 4) (26,39,40). The lung volume, unlike that in other interstitial diseases, mostly remains normal or may even be increased (38,39). As the disease progresses, the radiographic features gradually metamorphose from a reticulonodular pattern to a honeycomblike pattern corresponding to the summation of air-filled cysts (Fig 5). Rare findings in pulmonary Langerhans cell histiocytosis are pleural effusion and mediastinal and hilar lymphadenopathy (39,41).

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   Figure 4a.  Initial imaging findings of pulmonary Langerhans cell histiocytosis. (a) Posteroanterior chest radiograph obtained in a 9-month-old boy shows interstitial lung disease characterized by a diffuse and symmetric reticulonodular pattern with relative sparing of the costophrenic angles. (b) Chest CT scan (lung window settings) obtained in a 13-month-old girl with multisystem Langerhans cell histiocytosis depicts multiple bilateral small nodules (black arrow), some of which show early signs of excavation (white arrow). These features are suggestive of pulmonary involvement in Langerhans cell histiocytosis.

View larger version (109K): [in this window] [in a new window] [Download PPT slide]   Figure 4b.  Initial imaging findings of pulmonary Langerhans cell histiocytosis. (a) Posteroanterior chest radiograph obtained in a 9-month-old boy shows interstitial lung disease characterized by a diffuse and symmetric reticulonodular pattern with relative sparing of the costophrenic angles. (b) Chest CT scan (lung window settings) obtained in a 13-month-old girl with multisystem Langerhans cell histiocytosis depicts multiple bilateral small nodules (black arrow), some of which show early signs of excavation (white arrow). These features are suggestive of pulmonary involvement in Langerhans cell histiocytosis.

View larger version (151K): [in this window] [in a new window] [Download PPT slide]   Figure 5.  Imaging features of advanced-stage pulmonary involvement in a 17-year-old boy who previously was treated several times for acute manifestations of multisystem Langerhans cell histiocytosis. Posteroanterior chest radiograph shows the characteristic honeycomblike appearance produced by the summation of air-filled cysts. (Courtesy of K. Oudjhane, MD, Hospital for Sick Children, Toronto, Canada.)

Thin-section CT has proved valuable for the diagnosis and follow-up of pulmonary Langerhans cell histiocytosis (38,42). Children affected by the condition often are asymptomatic, and the subtle features of the disease—even in patients with an abnormal result of pulmonary function testing—may not be detectable on conventional chest radiographs. In such cases, the thin-section CT findings may be diagnostic. Multiple bilateral small nodules with early signs of excavation or cysts with varied wall thickness, especially when they are preferentially situated in the upper and middle lobes while the costophrenic angles are spared, are highly suggestive of Langerhans cell histiocytosis (38,43).

Findings at thin-section CT also may help exclude other possible diagnoses, such as lymphangioleiomyomatosis, emphysema, cystic bronchiectasis, sarcoidosis, and interstitial pneumonia (38,39,44) (Table 2). The thin-section CT features of lymphangioleiomyomatosis include evenly distributed small cysts with thin and well-defined walls and with a predominant location in the lung bases; pulmonary nodules are not seen. In emphysema, too, there is an absence of nodules and cysts. In cystic bronchiectasis, the cystic lesions exactly follow the course of the bronchial tree and are contiguous with one another. The thin-section CT features of sarcoidosis and interstitial pneumonia include small subpleural cysts, which produce a honeycomblike appearance. These cysts are generally accompanied by irreversible architectural distortion of the lung parenchyma because of fibrosis. In sarcoidosis, the cysts are predominantly apical in location, whereas the honeycomblike features associated with interstitial pneumonia predominate in the lung bases and costophrenic angles. The diffuse ground-glass opacities that generally are seen in active interstitial pneumonias are not associated with Langerhans cell histiocytosis. Sarcoidosis may be further characterized by perilymphatic nodules and mediastinal adenopathy, features that are not seen in pulmonary Langerhans cell histiocytosis (39).

Spontaneous pneumothorax from the rupture of a peripherally situated lung cyst may occur as an acute complication (sometimes, an initial manifestation) of pulmonary Langerhans cell histiocytosis and requires urgent treatment (26,34,38,45). Pneumomediastinum caused by leakage of air from the pulmonary interstices also may be observed (Fig 6).

View larger version (138K): [in this window] [in a new window] [Download PPT slide]   Figure 6.  Imaging features of recurrent pulmonary involvement in Langerhans cell histiocytosis in a 5-year-old boy with dyspnea and subcutaneous crepitation after treatment for multisystem disease in the lung, pituitary gland, and bone. Axial thin-section chest CT scan (lung window settings) depicts a left anterolateral spontaneous pneumothorax (small arrow) with associated pneumomediastinum (*) and substantial subcutaneous emphysema (large arrows) that extended into the cervical and abdominal soft tissues and the scrotum (not shown). The pervasive underlying cystic changes are indicative of advanced-stage pulmonary disease.

The chronic stage of pulmonary Langerhans cell histiocytosis typically is characterized by fibrosis (eg, stellate scars and surrounding cystic spaces of variable diameter) and traction emphysema, conditions that represent a combination of restrictive and obstructive mechanisms (29,34,42) (Fig 7). Pulmonary hypertension may result from extensive parenchymal destruction.

View larger version (164K): [in this window] [in a new window] [Download PPT slide]   Figure 7a.  Chronic pulmonary involvement in multisystem Langerhans cell histiocytosis in an 11-year-old boy (same patient as in Fig 6). (a) Posteroanterior chest radiograph shows a fibroemphysematous pattern predominantly in the right middle and both lower lung fields. (b) Thin-section chest CT scan (lung window settings) shows partly confluent thin-walled cystic air spaces with varied shapes and sizes, features indicative of irreversible damage to the lung.

View larger version (144K): [in this window] [in a new window] [Download PPT slide]   Figure 7b.  Chronic pulmonary involvement in multisystem Langerhans cell histiocytosis in an 11-year-old boy (same patient as in Fig 6). (a) Posteroanterior chest radiograph shows a fibroemphysematous pattern predominantly in the right middle and both lower lung fields. (b) Thin-section chest CT scan (lung window settings) shows partly confluent thin-walled cystic air spaces with varied shapes and sizes, features indicative of irreversible damage to the lung.

Lung involvement in Langerhans cell histiocytosis is not necessarily associated with an adverse outcome (26,34). However, the cystic lesions, emphysema, and fibrotic changes observed on radiologic images are persistent (Fig 7). In addition, the potentially toxic effects of chemotherapy or radiation therapy may lead to late-stage lung sequelae (26,46). Such sequelae may be distinguished from recurrent Langerhans cell histiocytosis only by closely comparing the most recent pulmonary imaging findings with earlier findings and with due consideration to the clinical evolution, the time and duration of chemo- or radiation therapy, and the particular thoracic region to which radiation therapy was applied. In equivocal cases, a lung biopsy may be necessary.

Thymic Involvement
Thymic involvement in Langerhans cell histiocytosis has been reported infrequently (18,23, 25,47). However, it probably has occurred more often than it has been recognized (48). All of the reported occurrences were associated with multisystem Langerhans cell histiocytosis (23). In many cases, there was coexistent pulmonary involvement (47).

Histiocytic infiltration increases the size of the thymus, and the thymic enlargement may be noticeable even on initial chest radiographs (Fig 8a). CT provides clearer depiction of the heterogeneously attenuating, diffusely enlarged thymus. Contrast-enhanced septa also may be seen within the thymus at CT (18). The contours of the organ remain smooth and lobulated. Punctate or serpentine calcifications are typical features (23,26,47) (Fig 8b) but are not always present (18). The calcifications may be of vascular or dystrophic origin; their exact pathogenesis is not known. Cystic areas corresponding to focal lesions also may be observed within the enlarged thymus (23,47). Areas of low attenuation at CT and signal hyperintensity at T1-weighted MR imaging without fat suppression (Fig 8c) correspond to areas of fatty replacement of the normal thymic tissue as a result of fibroxanthomatous reaction.

View larger version (90K): [in this window] [in a new window] [Download PPT slide]   Figure 8a.  Evolution of histiocytic infiltration of the thymus in a girl with multisystem Langerhans cell histiocytosis diagnosed at the age of 6 months. (a) Anteroposterior chest radiograph shows a diffuse interstitial lung disease pattern suggestive of pulmonary Langerhans cell histiocytosis. The thymus may be enlarged, but that is difficult to determine on the basis of conventional radiography alone. (b) Contrast-enhanced chest CT scan (mediastinal window settings) shows a heterogeneous upper anterior mediastinal mass with diffuse low attenuation and multiple calcifications (arrow), features suggestive of thymic involvement in Langerhans cell histiocytosis. (c) Coronal T1-weighted MR image obtained without fat suppression clearly depicts extension of the mass (arrow) to the thoracic inlet and the supraclavicular region. The heterogeneous high signal intensity within the mass corresponds to areas of substantial replacement of healthy thymic tissue by fat; regions with lower signal intensity represent calcifications. (d) Posteroanterior chest radiograph obtained 1 year later, 7 months after the end of systemic chemotherapy, shows complete resolution of the thymic enlargement when compared with the initial radiograph. Note the persistence of the pulmonary interstitial pattern suggestive of Langerhans cell histiocytosis.

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 8b.  Evolution of histiocytic infiltration of the thymus in a girl with multisystem Langerhans cell histiocytosis diagnosed at the age of 6 months. (a) Anteroposterior chest radiograph shows a diffuse interstitial lung disease pattern suggestive of pulmonary Langerhans cell histiocytosis. The thymus may be enlarged, but that is difficult to determine on the basis of conventional radiography alone. (b) Contrast-enhanced chest CT scan (mediastinal window settings) shows a heterogeneous upper anterior mediastinal mass with diffuse low attenuation and multiple calcifications (arrow), features suggestive of thymic involvement in Langerhans cell histiocytosis. (c) Coronal T1-weighted MR image obtained without fat suppression clearly depicts extension of the mass (arrow) to the thoracic inlet and the supraclavicular region. The heterogeneous high signal intensity within the mass corresponds to areas of substantial replacement of healthy thymic tissue by fat; regions with lower signal intensity represent calcifications. (d) Posteroanterior chest radiograph obtained 1 year later, 7 months after the end of systemic chemotherapy, shows complete resolution of the thymic enlargement when compared with the initial radiograph. Note the persistence of the pulmonary interstitial pattern suggestive of Langerhans cell histiocytosis.

View larger version (155K): [in this window] [in a new window] [Download PPT slide]   Figure 8c.  Evolution of histiocytic infiltration of the thymus in a girl with multisystem Langerhans cell histiocytosis diagnosed at the age of 6 months. (a) Anteroposterior chest radiograph shows a diffuse interstitial lung disease pattern suggestive of pulmonary Langerhans cell histiocytosis. The thymus may be enlarged, but that is difficult to determine on the basis of conventional radiography alone. (b) Contrast-enhanced chest CT scan (mediastinal window settings) shows a heterogeneous upper anterior mediastinal mass with diffuse low attenuation and multiple calcifications (arrow), features suggestive of thymic involvement in Langerhans cell histiocytosis. (c) Coronal T1-weighted MR image obtained without fat suppression clearly depicts extension of the mass (arrow) to the thoracic inlet and the supraclavicular region. The heterogeneous high signal intensity within the mass corresponds to areas of substantial replacement of healthy thymic tissue by fat; regions with lower signal intensity represent calcifications. (d) Posteroanterior chest radiograph obtained 1 year later, 7 months after the end of systemic chemotherapy, shows complete resolution of the thymic enlargement when compared with the initial radiograph. Note the persistence of the pulmonary interstitial pattern suggestive of Langerhans cell histiocytosis.

View larger version (106K): [in this window] [in a new window] [Download PPT slide]   Figure 8d.  Evolution of histiocytic infiltration of the thymus in a girl with multisystem Langerhans cell histiocytosis diagnosed at the age of 6 months. (a) Anteroposterior chest radiograph shows a diffuse interstitial lung disease pattern suggestive of pulmonary Langerhans cell histiocytosis. The thymus may be enlarged, but that is difficult to determine on the basis of conventional radiography alone. (b) Contrast-enhanced chest CT scan (mediastinal window settings) shows a heterogeneous upper anterior mediastinal mass with diffuse low attenuation and multiple calcifications (arrow), features suggestive of thymic involvement in Langerhans cell histiocytosis. (c) Coronal T1-weighted MR image obtained without fat suppression clearly depicts extension of the mass (arrow) to the thoracic inlet and the supraclavicular region. The heterogeneous high signal intensity within the mass corresponds to areas of substantial replacement of healthy thymic tissue by fat; regions with lower signal intensity represent calcifications. (d) Posteroanterior chest radiograph obtained 1 year later, 7 months after the end of systemic chemotherapy, shows complete resolution of the thymic enlargement when compared with the initial radiograph. Note the persistence of the pulmonary interstitial pattern suggestive of Langerhans cell histiocytosis.

The differential diagnosis of a low-attenuation thymic mass with enhancing septa should include multilocular thymic cyst caused by HIV infection. In the presence of an HIV infection, any associated pulmonary cystic lesions might be caused by an infectious agent such as Pneumocystis carinii (18). The differential diagnosis also should include anterior mediastinal tumors such as thymoma and teratoma, massive confluent lymphadenopathy, and rebound thymic hyperplasia (47) (Table 2). However, the calcifications that occur in teratomas are coarse and easily detected on chest radiographs, unlike the subtle punctate and serpentine calcifications that occur in thymic Langerhans cell histiocytosis (Fig 8b), features that are visible only at CT.

In general, thymic enlargement, calcifications, and cystic spaces completely resolve after chemotherapy (Fig 8d) (23,46). One reported case of isolated thymic involvement in Langerhans cell histiocytosis spontaneously resolved without any treatment (49).

Hepatobiliary Involvement
Hepatobiliary involvement occurs mainly in multisystem Langerhans cell histiocytosis. It is seen in 50%–60% of children with multisystem disease (50) but in only 14.4%–18% of those affected by Langerhans cell histiocytosis generally (50,51).

Langerhans cells directly infiltrate the periportal regions of the liver, showing a marked affinity for the bile ducts (51). Radiologic findings of liver involvement reflect the underlying histopathologic process, which comprises four phases of progression, from an initial proliferative phase to granulomatous, xanthomatous, and, finally, fibrous phases.Progression may occur despite treatment (50,52–54). However, in some cases, chemotherapy results in disease regression (Fig 9).

View larger version (120K): [in this window] [in a new window] [Download PPT slide]   Figure 9a.  Evolution of histiocytic infiltration of the liver parenchyma in a boy with multisystem Langerhans cell histiocytosis diagnosed at the age of 2 years. (a) Axial contrast-enhanced abdominal CT scan, obtained soon after the initial clinical manifestations of disease, shows hepatosplenomegaly. The linear areas of hypoattenuation along the portal tracts (large arrow) and the apparent small hypoattenuating nodules in both liver lobes (small arrows) represent portal triaditis due to histiocytic infiltration. (b) Axial contrast-enhanced abdominal CT scan obtained 2 years later shows regression of the periportal lesions in response to systemic chemotherapy. (c) Axial contrast-enhanced abdominal CT scan obtained 1 year after b, during an evaluation for clinical recurrence of Langerhans cell histiocytosis, shows lobular areas of hypoattenuation throughout the liver parenchyma without periportal abnormalities. Because the results of a liver biopsy were negative for Langerhans cells, the hypoattenuating features were believed to represent circumscribed areas of fatty infiltration. (d) Axial contrast-enhanced abdominal CT scan obtained 2 years after c, after a further course of chemotherapy, shows a complete regression of fatty infiltration and persistence of hepatosplenomegaly.

View larger version (101K): [in this window] [in a new window] [Download PPT slide]   Figure 9b.  Evolution of histiocytic infiltration of the liver parenchyma in a boy with multisystem Langerhans cell histiocytosis diagnosed at the age of 2 years. (a) Axial contrast-enhanced abdominal CT scan, obtained soon after the initial clinical manifestations of disease, shows hepatosplenomegaly. The linear areas of hypoattenuation along the portal tracts (large arrow) and the apparent small hypoattenuating nodules in both liver lobes (small arrows) represent portal triaditis due to histiocytic infiltration. (b) Axial contrast-enhanced abdominal CT scan obtained 2 years later shows regression of the periportal lesions in response to systemic chemotherapy. (c) Axial contrast-enhanced abdominal CT scan obtained 1 year after b, during an evaluation for clinical recurrence of Langerhans cell histiocytosis, shows lobular areas of hypoattenuation throughout the liver parenchyma without periportal abnormalities. Because the results of a liver biopsy were negative for Langerhans cells, the hypoattenuating features were believed to represent circumscribed areas of fatty infiltration. (d) Axial contrast-enhanced abdominal CT scan obtained 2 years after c, after a further course of chemotherapy, shows a complete regression of fatty infiltration and persistence of hepatosplenomegaly.

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   Figure 9c.  Evolution of histiocytic infiltration of the liver parenchyma in a boy with multisystem Langerhans cell histiocytosis diagnosed at the age of 2 years. (a) Axial contrast-enhanced abdominal CT scan, obtained soon after the initial clinical manifestations of disease, shows hepatosplenomegaly. The linear areas of hypoattenuation along the portal tracts (large arrow) and the apparent small hypoattenuating nodules in both liver lobes (small arrows) represent portal triaditis due to histiocytic infiltration. (b) Axial contrast-enhanced abdominal CT scan obtained 2 years later shows regression of the periportal lesions in response to systemic chemotherapy. (c) Axial contrast-enhanced abdominal CT scan obtained 1 year after b, during an evaluation for clinical recurrence of Langerhans cell histiocytosis, shows lobular areas of hypoattenuation throughout the liver parenchyma without periportal abnormalities. Because the results of a liver biopsy were negative for Langerhans cells, the hypoattenuating features were believed to represent circumscribed areas of fatty infiltration. (d) Axial contrast-enhanced abdominal CT scan obtained 2 years after c, after a further course of chemotherapy, shows a complete regression of fatty infiltration and persistence of hepatosplenomegaly.

View larger version (118K): [in this window] [in a new window] [Download PPT slide]   Figure 9d.  Evolution of histiocytic infiltration of the liver parenchyma in a boy with multisystem Langerhans cell histiocytosis diagnosed at the age of 2 years. (a) Axial contrast-enhanced abdominal CT scan, obtained soon after the initial clinical manifestations of disease, shows hepatosplenomegaly. The linear areas of hypoattenuation along the portal tracts (large arrow) and the apparent small hypoattenuating nodules in both liver lobes (small arrows) represent portal triaditis due to histiocytic infiltration. (b) Axial contrast-enhanced abdominal CT scan obtained 2 years later shows regression of the periportal lesions in response to systemic chemotherapy. (c) Axial contrast-enhanced abdominal CT scan obtained 1 year after b, during an evaluation for clinical recurrence of Langerhans cell histiocytosis, shows lobular areas of hypoattenuation throughout the liver parenchyma without periportal abnormalities. Because the results of a liver biopsy were negative for Langerhans cells, the hypoattenuating features were believed to represent circumscribed areas of fatty infiltration. (d) Axial contrast-enhanced abdominal CT scan obtained 2 years after c, after a further course of chemotherapy, shows a complete regression of fatty infiltration and persistence of hepatosplenomegaly.

During the proliferative and granulomatous phases, the infiltration of Langerhans cells and other inflammatory cells causes periportal inflammation with edema, which appears as bandlike or nodular areas of relative hypoechogenicity at US, hypoattenuation at CT (Fig 9a), and moderate to high signal intensity at T2-weighted MR imaging. Associated periportal contrast enhancement may be suggestive of portal triaditis (17,21). Further progression to the xanthomatous phase is characterized by linear periportal abnormalities and the formation of lipid-laden nodules in the liver parenchyma. The nodules appear hyperechoic at US (Fig 10), hypoattenuating at CT, and hyperintense at unenhanced T1-weighted MR imaging without fat suppression (17,19,55). These appearances are due to the foamy consistency of the histiocytes during this phase, an attribute caused by their ingestion of fat-containing cell membrane debris. The final, fibrous phase typically is represented by a dysmorphic and nodular appearance of the liver parenchyma—an appearance caused by extensive concentric periductal fibrosis and micronodular biliary cirrhosis—with secondary portal hypertension (19,50,52,54). Primary or secondary sclerosing cholangitis may produce extra- and intrahepatic biliary irregularities with segmental narrowing and focal areas of slight dilatation, resulting in a beaded appearance of the bile ducts at conventional cholangiography (14), ERCP, or MR cholangiopancreatography (Fig 11). The precise mechanism by which Langerhans cell histiocytosis leads to sclerosing cholangitis is not known. Most likely, bile duct injury and destruction result from direct histiocytic infiltration (50–52).

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 10.  Biopsy-proved hepatic involvement in multisystem Langerhans cell histiocytosis in a 4-year-old girl. Axial US image clearly depicts linear areas of hyperechogenicity (arrows) around several branches of the right portal vein, findings that probably represent the xanthomatous phase of histiocytic infiltration.

View larger version (83K): [in this window] [in a new window] [Download PPT slide]   Figure 11.  Biliary involvement in multisystem Langerhans cell histiocytosis in a 14-year-old boy. MR cholangiopancreatogram shows sclerosing cholangitis with involvement of both the intra- and extrahepatic ducts, a typical feature of biliary involvement in Langerhans cell histiocytosis. Note the beaded appearance of the intrahepatic ducts, which is caused mainly by segmental irregularities and narrowing, with minor focal dilatation. The extrahepatic bile duct is moderately dilated (8–10 mm) and slightly irregular.

The final stage is liver failure. At this stage, orthotopic liver transplantation is the only potentially curative treatment. To our knowledge, none of the children who are reported to have received a liver transplant for treatment of this condition have experienced a recurrence of hepatic Langerhans cell histiocytosis; however, acute rejection of the transplanted liver is common (50,56).

Children with direct liver infiltration by Langerhans cells initially present with hepatomegaly and biologic signs of liver dysfunction, especially cholestasis. Associated splenomegaly, either caused by portal hypertension resulting from periportal fibrosis or secondary to direct histiocytic infiltration, is another frequent manifestation. Jaundice also may be seen (21,50,51).

Unfortunately, hepatomegaly in children is a common and nonspecific clinical finding (1,10). If it results from enlarged hilar lymph nodes that are causing extrinsic biliary compression and consequent dilatation of the intrahepatic bile ducts, then it is accompanied by jaundice. However, hepatomegaly also may occur as an indirect effect of a macrophage activation syndrome accompanying Langerhans cell histiocytosis elsewhere in the body. For example, a generalized activation of the cellular immune system may cause Kupffer cell hypertrophy and hyperplasia, with resultant hepatomegaly. In such cases, the condition is completely reversible with treatment (29,51).

Finally, it is important to bear in mind that hepatomegaly and steatosis may occur as adverse effects of systemic chemotherapy for Langerhans cell histiocytosis. Chemotherapeutic agents also may lead to anomalous or inaccurate results of liver function testing (Fig 9c).

The periportal abnormalities detected at US, CT, and MR imaging in children with hepatic Langerhans cell histiocytosis are not disease-specific features but should be interpreted in conjunction with the clinical history and the results of biopsy (19). Other diffuse infiltrating liver diseases, such as lymphoma, leukemia, or hepatitis, should be considered in the differential diagnosis.

The main differential diagnosis of sclerosing cholangitis in children includes underlying inflammatory bowel disease. Cholangiopathies caused by infectious agents such as cryptosporidium or HIV, ischemia, or mechanical causes, with the development of secondary sclerosing cholangitis, are less common (50) (Table 2).

Digestive Tract Involvement
Gastrointestinal involvement in Langerhans cell histiocytosis is exceedingly rare: It is reported to occur in 2%–6% of children with multisystem Langerhans cell histiocytosis, and the mean age at diagnosis is 6 months (age range, birth to 36 months) (8,57–59). However, its frequency of occurrence may have been underestimated because the clinical symptoms (vomiting, diarrhea, bloody stools, malabsorption, and failure to thrive) are not specific and may be ascribed to other causes (eg, adverse effects of chemotherapy in the context of Langerhans cell histiocytosis) (16,59,60).

Cutaneous, mucosal, and digestive tract involvement in Langerhans cell histiocytosis may be considered a single clinicopathologic entity: Gastrointestinal symptoms are preceded by or associated with a characteristic rash in 86% of patients affected by gastrointestinal involvement in Langerhans cell histiocytosis (57). Therefore, in children with histopathologically proved skin manifestations of Langerhans cell histiocytosis and with any symptom suggestive of gut involvement, early endoscopic biopsy is recommended (16,57,58,60,61).

Gastrointestinal lesions of Langerhans cell histiocytosis may occur in widely ranging sites, from the oral mucosa to the anal canal, with either a continuous or a regional distribution (59). Histiocytic infiltration of the intestinal wall results in large cell aggregates associated with an inflammatory infiltrate composed of eosinophils, lymphocytes, and macrophages that is preferentially situated in the mucosal glands (57). Initially, mucosal erosion and thickening occur in successive layers of the intestinal wall; later, mucosal atrophy and glandular destruction become evident (62).

Findings at conventional barium studies are nonspecific, resembling features seen in exudative enteropathies or inflammatory bowel diseases: loss of the typical mucosal pattern, with an appearance of coarsening and cobblestone features reflective of mucosal destruction, segmental luminal narrowing alternating with dilated segments, and increased separation of the loops because of edematous inflammation (29,57,60–62). Underlying infection, lymphoma, and malakoplakia also should be included in the differential diagnosis (62).

Cross-sectional modalities such as CT and MR imaging likewise depict few specific features: circumferential bowel wall thickening with pathologic mucosal contrast enhancement, possibly leading to alternating narrowing and dilatation of the lumen in neighboring segments; edematous infiltration of the mesenteric fat; and free fluid (Fig 12). In addition, a case of intestinal perforation was reported to have occurred as an acute complication of gut involvement in Langerhans cell histiocytosis (62).

View larger version (113K): [in this window] [in a new window] [Download PPT slide]   Figure 12.  Gastrointestinal involvement in multisystem Langerhans cell histiocytosis in a 2-year-old boy with diarrhea. Axial contrast-enhanced abdominal CT image shows diffuse bowel wall thickening and pathologic enhancement of the small bowel (large arrows), which is surrounded by a small amount of ascites (small arrow). Because these features may be seen in inflammatory bowel disease, infection, and trauma as well as in intestinal Langerhans cell histiocytosis, the diagnosis was based on the results of biopsy.

To our knowledge, there are no published reports about the usefulness of US for evaluating intestinal involvement in Langerhans cell histiocytosis. However, circumferential bowel wall thickening with submucosal edema due to Langerhans cell histiocytosis could well be detected with US, provided that only a small amount of intestinal gas is present.

Gastrointestinal manifestations of Langerhans cell histiocytosis may be indicative of severe multisystem disease, in which case the prognosis is relatively poor and aggressive systemic therapy is warranted (16,57–59). Clinical manifestations are long lasting, and surviving patients may experience symptoms for several years after treatment (57). Regression of active disease has been reported on the basis of a gradual return to a normal mucosal appearance observed in consecutive barium studies (61).

Central Nervous System Involvement
Involvement of the central nervous system occurs in 23%–35% of children with Langerhans cell histiocytosis, mostly in those affected by multisystem disease (8,24,62).

Histopathologically, histiocytosis may involve the pituitary and hypothalamus by direct extension from a focus in the sphenoid bone. However, histiocytic proliferation also may begin in the brain, where it apparently arises among the adventitial cells of blood vessels, initially creating perivascular histiocytic foci that later coalesce to form granulomatous masses. These may occur at any site in the central nervous system (eg, in the cerebral parenchyma, meninges, or spinal cord) (63).

MR imaging is the standard of reference for radiologic evaluation of the central nervous system. Neuropathologic patterns of Langerhans cell histiocytosis may be described according to whether the characteristic MR imaging features are space-occupying or degenerative in nature (64). Space-occupying lesions affect the hypothalamic-neurohypophyseal axis, the central nervous system site most commonly and often earliest involved in Langerhans cell histiocytosis (8,20,63,65,66). MR imaging findings have been correlated with symptoms of diabetes insipidus, which is the most frequent initial manifestation of central nervous system involvement in Langerhans cell histiocytosis and is therefore considered a clinical hallmark of the condition. Typically, the formation of Langerhans cell histiocytosis granulomas leads to a loss in the normally high signal intensity of the posterior neurohypophysis on T1-weighted MR images (Fig 13a). The normal physiologic signal hyperintensity is related to the presence of vasopressin-containing granules and generally indicates normal hypothalamic-neurohypophyseal axis function, as is suggested also by its presence in 90%–100% of healthy subjects and its absence in children with central diabetes insipidus (65). Furthermore, because of the histiocytic infiltration, the hypothalamus, the pituitary stalk, or both are frequently enlarged and demonstrate gradually increasing homogeneous enhancement after an intravenous injection of gadolinium, without subsequent washout (Fig 13b) (65–68).

View larger version (135K): [in this window] [in a new window] [Download PPT slide]   Figure 13a.  Multisystem Langerhans cell histiocytosis in a 2-year-old girl with diabetes insipidus. (a) Sagittal unenhanced T1-weighted MR image shows a signal loss in the normally high-signal-intensity neurohypophysis (black arrow) and thickening of the infundibulum (white arrow). (b) Sagittal contrast-enhanced T1-weighted MR image obtained after an intravenous injection of gadolinium shows intense enhancement of the enlarged pituitary stalk (arrow), a finding representative of Langerhans cell infiltration.

View larger version (137K): [in this window] [in a new window] [Download PPT slide]   Figure 13b.  Multisystem Langerhans cell histiocytosis in a 2-year-old girl with diabetes insipidus. (a) Sagittal unenhanced T1-weighted MR image shows a signal loss in the normally high-signal-intensity neurohypophysis (black arrow) and thickening of the infundibulum (white arrow). (b) Sagittal contrast-enhanced T1-weighted MR image obtained after an intravenous injection of gadolinium shows intense enhancement of the enlarged pituitary stalk (arrow), a finding representative of Langerhans cell infiltration.

The differential diagnosis includes other infundibular diseases, such as adenohypophysitis, which can be differentiated from Langerhans cell histiocytosis by a sharp increase in contrast enhancement and rapid washout after the administration of the intravenous contrast medium (64). Granulomatous diseases such as sarcoidosis, Wegener disease, and leukemia also must be considered in the differential diagnosis (68). Rarer entities that must be excluded include germ cell tumors (germinoma, teratoma) and hemangioblastoma. These diseases produce the same MR imaging features as does Langerhans cell histiocytosis, with the same pattern of enhancement at dynamic MR imaging (64).

The regression of pituitary thickening observed on MR images after treatment should not be taken as an indication of the clinical remission of diabetes insipidus, which generally persists. Diabetes insipidus is the most common sequela seen in patients with central nervous system involvement in Langerhans cell histiocytosis (67).

The second most frequent pattern of central nervous system involvement in Langerhans cell histiocytosis is characterized by intraaxial neuro-degenerative changes. Bilateral symmetric lesions in the cerebellum, especially the dentate nucleus (20), basal ganglia, or brainstem, are most often observed. Such lesions represent diffuse inflammatory brain damage. Consequent neuronal and axonal degeneration and secondary myelin loss result in atrophy, which mostly affects the cerebellar cortex and the white matter. These lesions show variable signal intensity on MR images, depending on the site and stage of disease (64). Initially, inflammation may lead to contrast enhancement of the tiny, sharply demarcated lesions (Fig 14), which, when compared with the background parenchyma, appear isointense on T1-weighted images and isointense or mildly hyperintense on T2-weighted images (20,68). As demyelination and gliosis occur, these lesions enlarge and take on the appearance of poorly defined patchy areas with high signal intensity on T2-weighted images and low signal intensity on unenhanced T1-weighted images. These areas show no contrast enhancement after intravenous injection of gadolinium and exhibit no space-occupying effect (24). The resultant MR imaging pattern resembles that seen in leukencephalopathy (64).

View larger version (171K): [in this window] [in a new window] [Download PPT slide]   Figure 14a.  Cerebral involvement in Langerhans cell histiocytosis in an 11-year-old boy. Sagittal contrast-enhanced T1-weighted MR images obtained after an intravenous injection of gadolinium depict small foci of pathologic enhancement in the anterior part of the midbrain (arrow in a) and in the cerebral peduncles (arrowhead in b), as well as cystic nodular enhancement and enlargement of the pineal gland (arrow in b).

View larger version (179K): [in this window] [in a new window] [Download PPT slide]   Figure 14b.  Cerebral involvement in Langerhans cell histiocytosis in an 11-year-old boy. Sagittal contrast-enhanced T1-weighted MR images obtained after an intravenous injection of gadolinium depict small foci of pathologic enhancement in the anterior part of the midbrain (arrow in a) and in the cerebral peduncles (arrowhead in b), as well as cystic nodular enhancement and enlargement of the pineal gland (arrow in b).

The differential diagnosis includes acute disseminated encephalomyelitis, acute multiphasic disseminated encephalitis, disseminated encephalitis, various metabolic and degenerative disorders, leukencephalopathy secondary to chemotherapy or radiation therapy, and paraneoplastic encephalitis (64) (Table 2). These entities can be distinguished from Langerhans cell histiocytosis only with reference to the clinical history and the results of biologic testing. At the initial stage, intraaxial lesions may be masslike, and tumors also should be included in the differential diagnosis.

In addition, hemophagocytic lymphohistiocytosis (class II of the pediatric histiocytic disorders) often manifests with central nervous system involvement, especially in the cerebellum. Like Langerhans cell histiocytosis, it also is typically signaled clinically by fever, hepatosplenomegaly, and cytopenia. MR imaging features that are characteristic of the acute stage of hemophagocytic lymphohistiocytosis include multiple areas of signal hyperintensity in the cerebellum and the periventricular white matter of both cerebral hemispheres on T2-weighted MR images. These high-signal-intensity lesions may show a subtle mass effect and may enhance after the intravenous injection of contrast material. Later, volume loss is seen and the ventricles appear enlarged (69).

Less frequently, Langerhans cell histiocytosis granulomas, which resemble tumors, are observed in the extraaxial space (in the meninges, pineal gland, choroid plexus, and spinal cord). At MR imaging, these lesions are characterized by intermediate signal intensity on T1- and T2-weighted images, with moderate or marked uniform intense contrast enhancement after intravenous gadolinium injection (64,68,70,71). The frequent appearance of pineal gland cysts and pineal enlargement in patients with Langerhans cell histiocytosis may reflect direct histiocytic infiltration or hyperplasia of the gland (64) (Fig 14b). The differential diagnosis of these extraaxial features includes lymphomatous, leukemic, and carcinomatous infiltrates (Table 2). Langerhans cell lesions of the choroid plexus, which may be calcified, must be distinguished from choroid plexus papillomas (68) and juvenile xanthogranulomas, which belong to class II of the histiocytic disorders. The class II histiocytic lesions occur, in general, in an older age group than does Langerhans cell histiocytosis, and they tend to be asymptomatic (69).

Head and Neck Involvement
Head and neck involvement in Langerhans cell histiocytosis is common and has been reported to occur in 60%–82% of patients, either as primary or secondary disease (22,72). The manifestations are diverse and may include bone and soft-tissue lesions, cervical lymphadenopathy (Fig 15), and skin rash (22,68). Because of the proximity of the various anatomic structures in the head and neck, lesions often are complex, involving multiple structures simultaneously (Fig 16). Craniofacial osseous destruction has occurred in association with adjacent soft-tissue infiltration in more than 50% of cases. Specific sites of soft-tissue involvement in Langerhans cell histiocytosis are highly variable and include the cavernous sinus, the orbits (Fig 17), the paranasal sinuses, the naso- and oropharynx, the temporal region with the masticator space and the ear, the larynx and hypopharynx, the thyroid and salivary glands, and the adjacent muscles (72).

View larger version (174K): [in this window] [in a new window] [Download PPT slide]   Figure 15.  Soft-tissue involvement in Langerhans cell histiocytosis in the neck of a 7-year-old boy. Sagittal US image of the left cervix shows bilateral homogeneously enlarged and confluent lymph nodes.

View larger version (120K): [in this window] [in a new window] [Download PPT slide]   Figure 16a.  Head and neck Langerhans cell histiocytosis in a 13-month-old boy. (a) Axial contrast-enhanced CT scan of the skull base shows a hypoattenuating soft-tissue mass (*) of the right temporo-occipital region with destructive osseous lesions of the mastoid and occipital bones (arrows). (b) Axial contrast-enhanced fat-saturated MR image shows bilateral temporal soft-tissue lesions that appear intensely enhanced (arrows) and contiguous regions of histiocytic infiltration in the right masticator space and both parotid glands anteriorly (*). (c) Coronal T2-weighted MR image depicts caudal extension of the bilateral temporal histiocytic infiltration (white arrows) into both sternocleidomastoid muscles (*) and extensive involvement of the right mastoid bone (black arrows) while the left is intact. (Case courtesy of K. Oudjhane, MD, Hospital for Sick Children, Toronto, Canada.)

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 16b.  Head and neck Langerhans cell histiocytosis in a 13-month-old boy. (a) Axial contrast-enhanced CT scan of the skull base shows a hypoattenuating soft-tissue mass (*) of the right temporo-occipital region with destructive osseous lesions of the mastoid and occipital bones (arrows). (b) Axial contrast-enhanced fat-saturated MR image shows bilateral temporal soft-tissue lesions that appear intensely enhanced (arrows) and contiguous regions of histiocytic infiltration in the right masticator space and both parotid glands anteriorly (*). (c) Coronal T2-weighted MR image depicts caudal extension of the bilateral temporal histiocytic infiltration (white arrows) into both sternocleidomastoid muscles (*) and extensive involvement of the right mastoid bone (black arrows) while the left is intact. (Case courtesy of K. Oudjhane, MD, Hospital for Sick Children, Toronto, Canada.)

View larger version (176K): [in this window] [in a new window] [Download PPT slide]   Figure 16c.  Head and neck Langerhans cell histiocytosis in a 13-month-old boy. (a) Axial contrast-enhanced CT scan of the skull base shows a hypoattenuating soft-tissue mass (*) of the right temporo-occipital region with destructive osseous lesions of the mastoid and occipital bones (arrows). (b) Axial contrast-enhanced fat-saturated MR image shows bilateral temporal soft-tissue lesions that appear intensely enhanced (arrows) and contiguous regions of histiocytic infiltration in the right masticator space and both parotid glands anteriorly (*). (c) Coronal T2-weighted MR image depicts caudal extension of the bilateral temporal histiocytic infiltration (white arrows) into both sternocleidomastoid muscles (*) and extensive involvement of the right mastoid bone (black arrows) while the left is intact. (Case courtesy of K. Oudjhane, MD, Hospital for Sick Children, Toronto, Canada.)

View larger version (135K): [in this window] [in a new window] [Download PPT slide]   Figure 17.  Head and neck involvement in Langerhans cell histiocytosis in a 3-year-old boy. Coronal T1-weighted MR image shows histiocytic infiltration of the left orbit with extension into the skull base (arrows) and ethmoid air cells (*).

CT is performed to evaluate the extent of osseous erosion or destruction, and MR imaging is used to evaluate the adjacent soft tissues. Compared with the surrounding muscles, soft-tissue masses have hyperintense signal on T2-weighted MR images and isointense to hypointense signal on T1-weighted images, and they show marked enhancement after the intravenous injection of gadolinium (15,72,73).

Involvement of the skull base may take two different forms: More commonly, the histiocytic infiltration is confined to the petrous portion of the temporal bone; less often, it arises elsewhere in the skull base (eg, the clivus). Soft-tissue masses invariably extend into the middle cranial fossa (15,73).

The ear is a common site of involvement, with a reported prevalence of 15%–61% among children with a diagnosis of Langerhans cell histiocytosis (15,74). Ear involvement most often manifests as chronic otorrhea, followed by mastoiditis, otitis, hearing loss, masses in the ear canal, or meatal skin involvement. Most patients who manifest ear involvement have multisystem disease (15,74). A radiologic finding of temporal bone destruction, especially of the mastoid, the external auditory meatus, or the middle or internal ear, is most often associated with an adjacent soft-tissue mass. Extradural extension may be seen adjacent to the temporal lobe (15).

Errors in diagnosing ear involvement in Langerhans cell histiocytosis are frequent because the otologic findings are similar to those in other conditions, particularly mastoiditis or refractory otitis media or externa (15,72,74).

The diagnosis of head and neck involvement in Langerhans cell histiocytosis may be difficult because the manifestations may mimic those in other inflammatory diseases, such as tuberculosis and sarcoidosis. The differential diagnosis also includes metastatic disease from neuroblastoma and leukemic deposits. Primary neoplastic processes such as chordoma, chondrosarcoma, and local extension of a nasopharyngeal carcinoma or pituitary tumor must be differentiated from skull base Langerhans cell histiocytosis. In cases of possible temporal involvement by Langerhans cell histiocytosis, rhabdomyosarcoma and mastoiditis must be considered within the differential diagnosis, although the latter is not associated with large soft-tissue masses or extensive bone destruction. The clinical or radiologic findings may be diagnostic of Langerhans cell histiocytosis, especially when bilateral involvement is present (Fig 16). Lymphoma and Rosai-Dorfman disease also may simulate head and neck Langerhans cell histiocytosis (Table 2). Rosai-Dorfman disease consists of sinus histiocytosis with massive lymphadenopathy and, possibly, massive cervical adenopathy and soft-tissue lesions of the head and neck, but it does not involve the skin (8,13,22). Rosai-Dorfman disease belongs to class II of the histiocytic disorders (Table 1).

Although head and neck lesions in Langerhans cell histiocytosis often are complex, the overall outcome after chemotherapy, which is the treatment of choice, has been described as good. However, recurrences are common, especially in patients with multisystem disease (15,72).

Salivary Gland Involvement
Langerhans cell histiocytosis of the salivary glands without involvement of adjacent anatomic structures is extremely rare. To our knowledge, the parotid gland is the only salivary gland in which this has occurred. In two reported cases, it manifested as painless bilateral swelling in children with previously diagnosed multisystem Langerhans cell histiocytosis (8,75). In one of the cases, cervical lymphadenopathy was found; however, no other anatomic structures of the head and neck region were involved in either case (75). The imaging features of parotid gland involvement, as depicted at US (Fig 18a) and CT (Fig 18b, 18c), include bilateral homogeneous enlargement of the gland without any areas of necrosis or calcification.

View larger version (160K): [in this window] [in a new window] [Download PPT slide]   Figure 18a.  Head and neck involvement in multisystem Langerhans cell histiocytosis in a 3-year-old boy with painless swelling of both parotid glands, the first clinical manifestation of disease. (a) Sagittal US image shows diffuse enlargement and hypoechogenicity of the right parotid gland (arrows). No cervical adenopathy was found at US. Langerhans cell histiocytic infiltration was confirmed at biopsy of the parotid lesion. (b) Axial contrast-enhanced CT scan depicts bilateral enhancement and enlargement of the parotid glands without necrosis or calcification (arrows). (c) Axial contrast-enhanced CT scan obtained 2 years later, after systemic chemotherapy, shows a normal size of the parotid glands (arrows), a finding indicative of complete regression of the histiocytic infiltration.

View larger version (126K): [in this window] [in a new window] [Download PPT slide]   Figure 18b.  Head and neck involvement in multisystem Langerhans cell histiocytosis in a 3-year-old boy with painless swelling of both parotid glands, the first clinical manifestation of disease. (a) Sagittal US image shows diffuse enlargement and hypoechogenicity of the right parotid gland (arrows). No cervical adenopathy was found at US. Langerhans cell histiocytic in-filtration was confirmed at biopsy of the parotid lesion. (b) Axial contrast-enhanced CT scan depicts bilateral enhancement and enlargement of the parotid glands without necrosis or calcification (arrows). (c) Axial contrast-enhanced CT scan obtained 2 years later, after systemic chemotherapy, shows a normal size of the parotid glands (arrows), a finding indicative of complete regression of the histiocytic infiltration.

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 18c.  Head and neck involvement in multisystem Langerhans cell histiocytosis in a 3-year-old boy with painless swelling of both parotid glands, the first clinical manifestation of disease. (a) Sagittal US image shows diffuse enlargement and hypoechogenicity of the right parotid gland (arrows). No cervical adenopathy was found at US. Langerhans cell histiocytic infiltration was confirmed at biopsy of the parotid lesion. (b) Axial contrast-enhanced CT scan depicts bilateral enhancement and enlargement of the parotid glands without necrosis or calcification (arrows). (c) Axial contrast-enhanced CT scan obtained 2 years later, after systemic chemotherapy, shows a normal size of the parotid glands (arrows), a finding indicative of complete regression of the histiocytic infiltration.

In children, bilateral parotid gland enlargement usually results from a benign cause, such as infection. Other entities that should be considered in the differential diagnosis include autoimmune disease, granulomatous inflammatory disease (tuberculosis, sarcoidosis), lymphoma, and Rosai-Dorfman disease (75) (Table 2).

Mucocutaneous Involvement
Mucocutaneous involvement is commonly seen and occurs in 50%–55%% of all cases of Langerhans cell histiocytosis (8). The skin is the second most frequently affected organ, after bone. Mucocutaneous involvement is not necessarily considered benign, because it progresses from localized to disseminated disease in many of those affected (8,10).

When the skin is the only organ involved in Langerhans cell histiocytosis, the patient is usually a male infant with an age of less than 1 year (26) (Fig 19).

View larger version (129K): [in this window] [in a new window] [Download PPT slide]   Figure 19a.  Extensive cutaneous involvement in Langerhans cell histiocytosis in a 9-month-old boy. No other sites of involvement were found at skeletal radiography, chest CT, abdominal US, or cerebral MR imaging. (a, b) Photographs show multiple erythematous red and brown papules on the skin in the necklace area and axillary folds (a) and on the scalp (b). Note the yellowish crusted nodular lesions in b, features typical of cutaneous Langerhans cell histiocytosis.

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   Figure 19b.  Extensive cutaneous involvement in Langerhans cell histiocytosis in a 9-month-old boy. No other sites of involvement were found at skeletal radiography, chest CT, abdominal US, or cerebral MR imaging. (a, b) Photographs show multiple erythematous red and brown papules on the skin in the necklace area and axillary folds (a) and on the scalp (b). Note the yellowish crusted nodular lesions in b, features typical of cutaneous Langerhans cell histiocytosis.

Skin involvement in Langerhans cell histiocytosis is characterized by erythematous maculopapular or nodular lesions, which are often seborrheic, brownish-yellowish, and crusted, especially when they occur in the retroauricular region and on the scalp (10). In addition to those areas, the rash predominantly affects the inguinal region, the axillary folds (Fig 19), the necklace area (the skin around the neck), and the lumbosacral region (1). The mucous membranes that are most frequently involved are those of the genitalia and oral vestibule (10). It may be difficult to distinguish a histiocytic rash from seborrheic dermatitis (1), and a biopsy may be necessary to achieve an accurate diagnosis.

	Summary

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Etiology and General Histologic... Imaging Features Summary References

 
Extraosseous involvement in Langerhans cell histiocytosis is much less common than osseous involvement. It may affect nearly any anatomic site and may include diverse combinations of manifestations that produce a broadly varied spectrum of imaging features, none of which is pathognomonic.

To facilitate diagnosis at an early stage, radiologists should be familiar with the most appropriate modality for imaging of each organ or system and with the imaging features that are suggestive of involvement of that organ or system. Chest radiography is generally used for the initial evaluation of patients suspected of having pulmonary involvement in Langerhans cell histiocytosis, but only CT (in particular, thin-section CT) is diagnostic of early-stage pulmonary disease. The severity of pulmonary Langerhans cell histiocytosis also may be assessed with thin-section CT because the findings correlate well with clinical measurements of functional impairment.

US is used to screen the abdominopelvic region, and any findings then may be reevaluated with spiral CT. For hepatobiliary involvement in Langerhans cell histiocytosis, MR imaging is the technique of choice, especially for the detection of associated sclerosing cholangitis.

MR imaging is also the modality primarily used for the evaluation of cerebral and spinal involvement in Langerhans cell histiocytosis and the further assessment of soft-tissue lesions (especially those in the head and neck) after initial screening with US. However, osseous involvement of the head and neck is best evaluated with CT.

	Footnotes

 

Abbreviations: ERCP = endoscopic retrograde cholangiopancreatography, HIV = human immunodeficiency virus

	References

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Etiology and General Histologic... Imaging Features Summary References

 

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