Langerhans Cell Granulomatosis Research Articles

High-resolution CT in smoking-related interstitial lung diseases.

In addition to chronic obstructive pulmonary disease (COPD) and bronchogenic carcinoma, smoking can also cause interstitial lung diseases (ILDs) such as respiratory bronchiolitis (RB), RB with ILD (RB-ILD), desquamative interstitial pneumonia (DIP), Langerhans cell granulomatosis (LCG) and idiopathic pulmonary fibrosis-usual interstitial pneumonia (IPF-UIP). However, smoking seems to have a protective effect against hypersensitivity pneumonitis (HP), sarcoidosis and organising pneumonia (OP). High-resolution computed tomography (HRCT) has a pivotal role in the differential diagnosis. RB is extremely frequent in smokers, and is considered a marker for smoking exposure. It has no clinical relevance in itself since most patients with RB are asymptomatic. It is frequent to observe the association of RB with other smoking-related diseases, such as LCG or pulmonary neoplasms. In RB-ILD, HRCT features are more conspicuous and diffuse than in RB, but there is no definite cut-off between the two entities and any distinction can only be made by integrating imaging and clinical data. RB, RB-ILD and DIP may represent different degrees of the same pathological process, consisting in a bronchiolar and alveolar inflammatory reaction to smoking. Smoking is also a well-known risk factor for pulmonary fibrosis. Multidisciplinary discussion and follow-up can generally solve even the most difficult cases.

Radiotherapy in langerhans cell histiocytosis - a rare indication in a rare disease

IntroductionLangerhans Cell Histiocytosis (LCH) represents a rare benign disorder, previously designated as “Histiocytosis X”, “Type II Histiocytosis” or “Langerhans Cell Granulomatosis”. Clinical presentation includes osteolysis, ulcerations of skin and soft tissues but also involvement of the CNS is described.Because treatment concepts are not well defined the German Cooperative Group on Radiotherapy for Benign Diseases performed a retrospective analysis.Methods and materialEight closely cooperating centres collected patients’ data of the past 45 years. As study endpoints disease free survival, recurrent disease, death and therapy related side effects were defined.ResultsA total of 80 patients with histologically proven LCH were irradiated within the past 45 years. According to the LCH classification of Greenberger et al. 37 patients had stage Ia, 21 patients stage Ib, 13 patients stage II and 9 patients stage IIIb and the median age was 29 years. The median Follow up was 54 months (range 9–134 months). A total of 39 patients had a surgical intervention and 23 patients a chemotherapy regimen.Radiation treatment was carried out with a median total dose of 15 Gy (range 3–50.4 Gy). The median single fraction was 2 Gy (range 1.8-3 Gy).Overall, 77% patients achieved a complete remission and 12.5% achieved a partial remission. The long-term control rate reached 80%. Within an actuarial overall 5-year survival of 90% no radiogenic side and late effects ≥EORTC/RTOG II° were observed.ConclusionIn the present study a large collective of irradiated patients was analysed. Radiotherapy (RT) is a very effective and safe treatment option and even low RT doses show sufficient local control.

Pulmonary Hypertension in Pulmonary Langerhans Cell Granulomatosis

Introduction. Pulmonary Langerhans cell granulomatosis is a rare disease with a variable course. In pulmonary Langerhans cell granulomatosis pulmonary hypertension is frequent and has an independent prognostic impact. A vasculopathy which ist not related to ventilatory disturbance and fibrosis has been identified. An arteriopathy and even a venulopathy have been described. Due to this possible venulopathy vasodilators carry a significant risk for pulmonary congestion and edema. No drugs have been approved until now. Case Presentation. One female with PLCG developed severe PH four years after primary diagnosis of pulmonary Langerhans cell granulomatosis. Retrospective analysis of lung biopsies revealed an arterial vasculopathy at the time of primary diagnosis without clinical signs of PH at this time. Sildenafil led to a sustained improvement of hemodynamic features and exercise capacity. Conclusion. This paper underlines that patients with PLCG with an arterial vasculopathy-related PH might improve under sildenafil. Further trials addressing treatment of PH and vasculopathy are needed.

Pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease (PVOD) is currently classified as a subgroup of pulmonary arterial hypertension (PAH) and accounts for 5-10% of cases initially considered to be idiopathic PAH. PVOD has been described as idiopathic or complicating other conditions, including connective tissue diseases, HIV infection, bone marrow transplantation, sarcoidosis and pulmonary Langerhans cell granulomatosis. PVOD shares broadly similar clinical presentation, genetic background and haemodynamic characteristics with PAH. Compared to PAH, PVOD is characterised by a higher male/female ratio, higher tobacco exposure, lower arterial oxygen tension at rest, lower diffusing capacity of the lung for carbon monoxide, and lower oxygen saturation nadir during the 6-min walk test. High-resolution computed tomography (HRCT) of the chest can be suggestive of PVOD in the presence of centrilobular ground-glass opacities, septal lines and lymph node enlargement. Similarly, occult alveolar haemorrhage is associated with PVOD. A noninvasive diagnostic approach using HRCT of the chest, arterial blood gases, pulmonary function tests and bronchoalveolar lavage could be helpful for the detection of PVOD patients and in avoiding high-risk surgical lung biopsy for histological confirmation. PVOD is characterised by a poor prognosis and the possibility of developing severe pulmonary oedema with specific PAH therapy. Lung transplantation is the treatment of choice. Cautious use of specific PAH therapy can, however, be helpful in some patients.

Présentation pulmonaire inhabituelle d’une histiocytose à cellules de Langerhans systémique

An 80-year-old nonsmoking man was referred to our hospital with bilateral perihilar pulmonary opacities. He had a history of epilepsy, sclerosing cholangitis, cutaneous lesions previously diagnosed as localised Langerhans cell histiocytosis. Symptoms included dry cough and dyspnea. Chest CT showed bilateral perihilar alveolar consolidation with bronchiectasis. Histological examination of a lung biopsy showed typical features of Langerhans cell granulomatosis. Investigations revealed anterior and posterior hypopituitarism. An important improvement occurred with corticosteroid and vinblastine treatment.

Signal Intensity Changes on MRI During the Healing Process of Spinal Langerhans Cell Granulomatosis

Two patients with spinal Langerhans cell granulomatosis were followed by magnetic resonance imaging, and the observed signal changes were detailed. Both patients had no neurologic abnormalities but back pain. They were treated by immobilization with a brace and bed rest. Their back pain disappeared after about a month. At the first visit, the tumorous lesions involving vertebrae showed mainly low signal intensity on T1-weighted imaging (T1WI) and high intensity on T2-weighted imaging (T2WI). They were clearly enhanced by gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA). Their original intensities changed to iso-intensities on both T1WI and T2WI without enhancement by Gd-DTPA after a year. These signal changes might indicate the healing stage of the involved vertebrae and recommend the removal of the spinal brace.

Pulmonary Langerhans Cell Granulomatosis: Clinical and Laboratory Data in 10 Greek Patients

Pulmonary Langerhans Cell Granulomatosis: Clinical and Laboratory Data in 10 Greek Patients

Expression of a functional eotaxin (CC chemokine ligand 11) receptor CCR3 by human dendritic cells.

Critical to the function of Ag-presenting dendritic cells (DCs) is their capacity to migrate to lymphoid organs and to sites of inflammation. A final stage of development, termed maturation, yields DCs that are strong stimulators of T cell-mediated immunity and is associated with a remodeling of the cell surface that includes a change in the levels of expression of many molecules, including chemokine receptors. We show in this study that CCR3, a chemokine receptor initially discovered on eosinophils, is also expressed by human DCs that differentiate from blood monocytes, DCs that emigrate from skin (epidermal and dermal DCs), and DCs derived from CD34+ hemopoietic precursors in bone marrow, umbilical cord blood, and cytokine-elicited peripheral blood leukapheresis. Unlike other chemokine receptors, such as CCR5 and CCR7, the expression of CCR3 is not dependent on the state of maturation. All DC subsets contain a large intracellular pool of CCR3. The surface expression of CCR3 is not modulated following uptake of particulate substances such as zymosan or latex beads. CCR3 mediates in vitro chemotactic responses to the known ligands, eotaxin and eotaxin-2, because the DC response to these chemokines is inhibited by CCR3-specific mAbs. We postulate that expression of CCR3 may underlie situations where both DCs and eosinophils accumulate in vivo, such as the lesions of patients with Langerhans cell granulomatosis.

Langerhans cell granulomatosis: a case report of polyostotic manifestation in the jaw

Abstract.We report the case of a 43-year-old woman who suffered from a polyostotic form of Langerhans cell granulomatosis (LCG) in the mandible and maxilla. The course of the disease was followed for more than 14 years. The disease's progression finally required subtotal resection of the mandible and reconstruction with a microvascular fibula graft. The literature is reviewed for diagnostic and treatment concepts based on the different stages of LCG.

Hypersegmentation of inflammatory cells in Langerhans cell granulomatosis.

Langerhans cell granulomatosis (LCG) is characterized by a mixture of Langerhans cells and eosinophils in varying proportions. The characteristic morphology of Langerhans cells have already been described in many articles, but little attention has been paid to inflammatory cells. We examined six cases of Langerhans cell granulomatosis, which had originally been diagnosed as eosinophilic granuloma. Inflammatory cells present in LCG showed hypersegmentation. Twenty percent to 70% of eosinophils had three or more segmented nuclei, and 10-25% of neutrophils had five or more segmented nuclei. Such findings have never been described, and we believe hypersegmentation to be a feature of LCG. Furthermore, we emphasize that eosinophils in LCG mimic neutrophils in ethanol-fixed preparations, and thus may be a pitfall in making a diagnosis in cytology and intraoperative consultation.

皮膚病変，歯肉潰ようを認めた肺好酸球性肉芽腫様Ｌａｎｇｅｒｈａｎｓ ｃｅｌｌ ｇｒａｎｕｌｏｍａｔｏｓｉｓの１症例

We report here a case of Langerhans cell granulomatosis resembling so-called pulmonary eosinophilic granuloma. Patient was a 38 year-old male with chief complaints of fever and general fatigue, and also showed skin lesions with crust and ulcer of gingiva. Chest X-ray film in hospitalization showed diffuse abnormal shadows which were not detected two months before the admission. In both lung fields, diffuse multiple small cystic lesions with thin wall, small nodules and patchy lesions were also seen on chest computed tomography. Abnormal shadows were dominant in upper lung fields. No other involvement of organs including bones were found by garium and bone scintigraphies.Biopsy specimens were obtained from transbronchial lung biopsy, skin and gingiva. Granuloma formation with Langerhans cells and eosinophils invasion were found in all biopsy specimens by hematoxylin-eosin staining and immunostaining against the S-100 protein. On the basis of these findings, we gave the preferable diagnosis of Langerhans cell granulomatosis rather than pulmonary eosinophilic granuloma, because the patient showed systemic involvement. However, main organ involved was the lung and the clinical findings were looked like pulmonary eosinophilic granuloma as a localized disease. Interestingly, without specific treatment excluding smoking cessation, clinical symptoms and chest X-ray abnormalities improved spontaneously in this case.

BILATERAL HYDRONEPHROSIS IN A PATIENT WITH ERDHEIM-CHESTER DISEASE

Erdheim-Chester disease is a rare systemic disorder, which involves the retroperitoneum and kidneys in almost a third of the cases. CASE REPORT A 68-year-old white man presented in October 1997 with persistent edema of the lower limbs associated with acute pulmonary edema. He had a history of breathlessness on exertion, which led to the diagnosis of histiocytosis X (Langerhans cell granulomatosis) in 1983, although lung biopsy failed to demonstrate X bodies. Hemoglobin was 10.2 gm./dl. (normal 12 to 16), erythrocyte sedimentation rate 100 (normal 4 to 8) and serum creatinine 130 mmol./l. (normal 50 to 100). Thoracic computerized tomography (CT) showed diffuse interstitial fibrosis, periaortic fibrosis of the descending thoracic aorta and bilateral adrenal hyperplasia. Abdominal CT and magnetic resonance imaging revealed bilateral hydronephrosis associated with right hilar lymphadenopathy (part A of figure), nonspecific adrenal hyperplasia (part B of figure) and retroperitoneal fibrosis at the level of L1 and L2 vertebrae. Excretory urography demonstrated a 3-hour delay in excretion from the left kidney, nonvisualization of the ureters and a heterogeneous appearance of the hips. Bilateral retrograde pyelography revealed bilateral lumbar ureteral stenosis extending 3 to 4 cm. below the ureteropelvic junction. A silicone double pigtail ureteral stent was inserted on both sides. Erdheim-Chester disease was confirmed on radiographs of the humerus, which showed specific signs, such as bilateral and symmetrical metaphyseal sclerosis, cortical thickening and medullary sclerosis. Endocrine tests were normal. CT guided biopsies failed to demonstrate specific histological features of Erdheim-Chester fibrosis. The patient received 1 mg./kg. prednisone daily for 6 months because of persistently elevated erythrocyte sedimentation rate and stable appearance of the fibrosis. He died of myocardial infarction in July 1998. Autopsy findings confirmed the diagnosis of Erdheim-Chester disease with specific pathological characteristics.

Spontaneous regression of orbital Langerhans cell granulomatosis in a three-year-old girl

PURPOSE: To report a case of spontaneous regression of orbital Langerhans cell granulomatosis.METHOD: Case report. A 3-year-old girl was initially examined with a 5-week history of slowly progressive blepharoptosis and periorbital swelling of the left eye.RESULTS: Computed tomographic scan showed a mass in the left orbit eroding into the left frontal bone; fine-needle aspiration confirmed diagnosis of Langerhans cell granulomatosis. After initial biopsy, the patient was treated by close observation alone. Six months after initial examination, the monostotic lesion had completely resolved.CONCLUSIONS: In some cases of monostotic Langerhans cell granulomatosis, initial biopsy followed by observation alone may allow for the spontaneous regression of the lesion. This conservative approach to treatment is an important therapeutic option that may spare the patient the adverse effects of surgical resection, radiation, or chemotherapy.

Oral Langerhans cell granulomatosis diagnosed merely by the presence of necrotizing gingivostomatitis

Oral Langerhans cell granulomatosis diagnosed merely by the presence of necrotizing gingivostomatitis

Langerhans Cell (Eosinophilic) Granulomatosis

We summarize our experience with 238 cases of Langerhans cell granulomatosis (LCG), 198 of whom were followed for a median period of 10.5 years. Our patients did well unless overtreated, and no deaths were attributed to the disorder itself. The disease may appear in unifocal or multifocal form, and treatment is based on this fact. Virtually all patients recovered completely except for occasional residual orthopedic problems or residual diabetes insipidus. Several of the patients underwent subsequent pregnancies without difficulty. The granulomas primarily occur in bone, but lung, skin, and lymph nodal involvement is not uncommon. Involvement of thyroid, thymus, and other sites is rare. The hallmark of the disease is the accumulation of Langerhans cells (LCs). We review the pathology of LCG by histology, electron microscopy, and immunolabeling. LCs originally were identified in squamous epithelium, but these cells are part of the widespread system of dendritic cells. The latter cells, which arise from CD34+ progenitors, are specialized and efficient antigen-presenting cells for T-cell-mediated immunity. In LCG, however, the major associated cells are not T cells, but mature eosinophils: hence the original name eosinophilic granuloma. Confusion about terminology has been based upon the scanty and rather crude pathology reports in the original literature. The term histiocytosis X was meant to cover a spectrum of three diseases--eosinophilic granuloma, Hand-Schüller-Christian disease (HSC), and Letterer-Siwe disease (LS)--but HSC and LS have no basis in pathology and hence the terms are meaningless. The term HSC has become a synonym for multifocal eosinophilic granuloma (LCG). The term LS has been used in reporting a number of benign, malignant, or unknown conditions. We prefer the term LCG to avoid confusion with the term histiocytosis X because there is evidence that the LC is not a member of the mononuclear phagocyte system and hence not a tissue macrophage, and because the use of the term "histiocyte" has become a convenience in much of the literature when reporting incompletely understood diseases.

Tobacco smoke induced lung granulomas and tumors: association with pulmonary langerhans cells

The density of zinc-iodide-osmium (ZIO) positive pulmonary Langerhans dendritic cells (LC) was increased about 20-fold in mice after passive exposure to tobacco smoke. This was associated with pulmonary changes consistent with the cigarette smoking-related clinical syndrome in humans, pulmonary Langerhans cell granulomatosis. The major feature was an interstitial peribronchial granuloma. The cellular infiltrate of the granuloma (lymphocytes, plasma cells, eosinophils, clusters of large histiocyte-like cells and macrophages) extended into the adjacent alveolar septum forming a star-shaped lesion. The histiocyte-like cells were large with pale acidophilic cytoplasm and many ill-defined short dendrites extending from the cell membrane. Bronchial epithelial metaplasia also developed. The interstitial changes were followed by the development of proliferative alveolar and bronchial lesions in 2 mice. The zinc-iodide-osmium positive cells were consistent with la positive pulmonary dendritic cells and their ultrastructure was similar to that of pulmonary Langerhans cells. After ceasing exposure to tobacco smoke the density of pulmonary Langerhans cells returned to that of the control level; interstitial granulomatous lesions disappeared, but the bronchial epithelial metaplasia did not reverse. Tobacco smoke exposure of mice produces interstitial granulomatous inflammation similar to Langerhans cell granulomatosis in humans. The elevated level of pulmonary Langerhans cells implicate these cells in the pathogenesis of these lesions.

Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases.

We report the clinical and histologic findings of lung biopsies from 48 patients with pulmonary Langerhans cell granulomatosis (PLCG) and show how special techniques such as immunohistochemistry, electron microscopy (EM), and high resolution computerized tomography (HRCT) of the lungs can be useful in diagnostically challenging cases. Nineteen patients were men and 29 were women. The median age was 33 years (range 15-54 years). Two had pituitary involvement. Bone lesions were observed in four patients and biopsy proven in two. All patients were cigarette smokers. In six patients HRCT revealed a combination of thin-walled cystic and nodular lesions. The pathologic diagnosis was established on the basis of open lung biopsy specimens in 44 cases and transbronchial biopsy specimens in 4 of 10 cases. In two transbronchial biopsies, diagnostic PLCG infiltrates were seen in toluidine blue-stained thick sections in the tissue processed for EM but not on the tissue processed for histology. EM in both of these cases revealed Birbeck granules within LCs. The diagnosis was supported by a positive bone biopsy in one of these patients and characteristic HRCT findings in the other. The antibody to S100 protein stained the LC infiltrates in the five cases studied. This staining and the characteristic findings on HRCT confirmed the diagnosis in one case in which the PLCG lesions were obscured by atelectasis. The frequent finding of intraluminal fibrosis (78% of open lung biopsies) supports the recent suggestion that this alteration plays an important role in the pathogenesis of fibrotic remodeling in PLCG. The strong association of PLCG with cigarette smoking and the frequent peribronchiolar location of PLCG lesions (87% of open lung biopsies) in our cases are consistent with the concept that in adults this disorder is associated with an abnormal response to cigarette smoke.

Pulmonary immune cells: villains and confederates

Over the past ten years or so, we have been witnessing a slow but enduring change of mainstream research in respiratory medicine. From being widely dominated by studies of lung function and pulmonary physiology, research in respiratory medicine has begun to move into the complex field of cellular and molecular biology, in its effort to understand the basic mechanisms of disease. This progress has been due not only to advances in immunological and biological science but also to the introduction of the bronchoalveolar lavage (BAL) procedure which provides access to the various cell populations of the lower respiratory tract This issue of the Journal contains the first of a series of reviews planned to highlight the recent knowledge on pulmonary immune cells in health and disease [1]. Written by experts fully familiar with the modem laboratory techniques applied to the studies of immune cells, each of the ar1icles will be devoted to a specific cell type, including dendritic cells, macrophages, lymphocytes, neutrophils, eosinophils, mast cells, and platelets. Their beneficial role in host defence against invading pathogens, but also their harmful effects in chronic lung injury, will be addressed. The series will describe the origin. maturation and differentiation of the cells, surface antigens and receptor repertoires, enzyrre and mediator oontents, as well as the mechanisms of cellular recruit:rrent and activation. In addition to biological cell functions such as secretion of lipid mxliators and cytokines, migration, ~ and interactions with other cells, the potentially deleterious role in the pathogenesis of human diseases, will be summarized with an emphasis on respiratory disorders. Lastly, the potential implications for therapeutic strategies based on this new approach to lung diseases will be assessed. The article appearing in this issue deals with dendritic cells and Langerhans cells [1]. Langerhans cells are thought to be derived from dendritic cells. However, they differ from dendritic cells, since the latter are characterized by typical cytoplasmic ~lies called Birbeck granules, visible only by electron microscopy. Both cells are potent accessory cells or antigen-presenting cells and stimulate Iymphocyte proliferation, whereas alveolar macrophages function rather poorly in this respect [2] . An important lung disease, eosinophilic granuloma or histiocytosis X, has been renamed Langerhans cell granulomatosis, following the recognition that the offending cell is the LangedJans cell. Cltrrent concepts suggest that the disease results from an abnormal immune response in cigarette smokers, initiated and maintained by Langerhans cells [1].

An immunoperoxidase study of S-100 protein distribution in normal and neoplastic tissues.

The presence of S-100 protein was immunohistochemically studied in many types of formalin-fixed and paraffin-embedded tumors (260 cases). Peripheral nerve tumors, i.e., schwannomas, neurofibromas, granular cell tumors, and neurogenic sarcomas were demonstrated to contain variable amounts of S-100 protein in the tumor cell cytoplasm and nuclei. In ganglioneuromas and ganglioneuroblastomas, neoplastic Schwann cells or satellite cells were positive for S-100 protein. About one-half of the cases of carcinoid tumors stained weakly for S-100 protein. In addition to these nervous tissue and carcinoid tumors, chondrosarcoma, chordomas, pleomorphic adenomas of the salivary gland, and Langerhans cell granulomatosis were also shown to produce S-100 protein. In many types of breast tumors and other lesions, S-100 protein positive cells were likely to correspond to the distribution of myoepithelial cells. These results indicate that S-100 protein is not strictly specific to nervous tissue and its tumors; however, the immunohistochemical demonstration of S-100 protein can be a useful diagnostic tool in tumor diagnosis.

Langerhans' cell granulomatosis (histiocytosis X) of bone in adults.

Langerhans' cell granulomatosis (LCG) (histiocytosis X) of bone is generally considered a childhood disease. A series of 61 adult patients who presented with histologically confirmed skeletal disease was studied. The male-to-female ratio was 2.1, and 36 patients were more than 30 years old, the oldest being 71 years. Pain was the most frequent symptom. Forty-six patients has solitary lesions, six had two or three, and nine had more than three. The time interval between the development of lesions, although usually less than 2 years, ranged up to 32 years. Rib, skull, and pelvis were the most frequently involved sites. Eight patients had extraskeletal disease. Radiologically, a well-defined lytic lesion, either with no surrounding reaction or with sclerotic margins, was seen most often. The rare, poorly defined lesions tended to occur in the clavicle. Microscopically, typical Langerhans' cells were present in large numbers. Eosinophils were usually prominent. Benign giant cells, mitotic figures, and necrosis also were observed. There was no histologic difference between solitary and multiple lesions. Surgery, radiation therapy, or a combination of both usually provided adequate treatment. Only two of the solitary lesions recurred. Eleven patients suffered from chronic, progressive disease, which inconsistently responded to treatment. None of the patients in our series died of the disease.