Robert Vassallo, Jay H Ryu, Darrell R Schroeder, Paul A Decker, Andrew H Limper
Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults.
N Engl J Med. 2002 Feb 14;346(7):484-90. doi: 10.1056/NEJMoa012087.
Abstract/Text
BACKGROUND: Pulmonary Langerhans'-cell histiocytosis is an uncommon interstitial lung disease in adults. It has an unpredictable course and may be associated with an increased susceptibility to the development of malignant neoplasms.
METHODS: We reviewed the records of 102 adults with histopathologically confirmed pulmonary Langerhans'-cell histiocytosis to ascertain their vital status and whether cancer had been diagnosed. The health status of surviving patients was quantified with the use of the 36-Item Short-Form General Health Survey. Factors potentially associated with survival after the diagnosis of pulmonary Langerhans'-cell histiocytosis were analyzed with the Cox proportional-hazards model.
RESULTS: The median follow-up period was 4 years (range, 0 to 23). There were 33 deaths, 15 of which were attributable to respiratory failure. Six hematologic cancers were diagnosed. The overall median survival was 12.5 years, which was significantly shorter than that expected for persons of the same sex and calendar year of birth (P<0.001). In a univariate analysis, variables predictive of shorter survival included an older age (P=0.003), a lower forced expiratory volume in one second (FEV1) (P=0.004), a higher residual volume (P=0.007), a lower ratio of FEV1 to forced vital capacity (P=0.03), and a reduced carbon monoxide diffusing capacity (P=0.001).
CONCLUSIONS: The survival of adults with pulmonary Langerhans'-cell histiocytosis is shorter than that in the general population, and respiratory failure accounts for a substantial proportion of deaths among such patients.
A Tazi
Adult pulmonary Langerhans' cell histiocytosis.
Eur Respir J. 2006 Jun;27(6):1272-85. doi: 10.1183/09031936.06.00024004.
Abstract/Text
Adult pulmonary Langerhans' cell histiocytosis is a rare disorder of unknown aetiology that occurs predominantly in young smokers, with an incidence peak at 20-40 yrs of age. In adults, pulmonary involvement with Langerhans' cell histiocytosis usually occurs as a single-system disease and is characterised by focal Langerhans' cell granulomas infiltrating and destroying distal bronchioles. High-resolution computed tomography (HRCT) of the chest is essential to the diagnosis, typically showing a combination of nodules, cavitated nodules, and thick- and thin-walled cysts. A high macrophage count in bronchoalveolar lavage (BAL) fluid is a common but nonspecific finding that merely reflects exposure to tobacco smoke. BAL is useful for eliminating infections and the other infiltrating lung disorders that can be seen in young adults. Langerhans' cells can be identified in BAL fluid, but, in contrast to what was initially hoped, this test shows a very low sensitivity and is rarely useful in the diagnosis of the disease. The definite diagnosis of pulmonary Langerhans' cell histiocytosis requires identification of Langerhans' cell granulomas, which is usually achieved by surgical lung biopsy at a site selected by chest HRCT. In practice, however, lung biopsy is performed on a case-by-case basis. No effective treatment is available to date, and improved understanding of the mechanisms involved in the pathogenesis of pulmonary Langerhans' cell histiocytosis is urgently needed, and should help in the development of specific therapeutic strategies for patients with this orphan disease.
N Mogulkoc, A Veral, P W Bishop, U Bayindir, C A Pickering, J J Egan
Pulmonary Langerhans' cell histiocytosis: radiologic resolution following smoking cessation.
Chest. 1999 May;115(5):1452-5.
Abstract/Text
We describe two patients with histologically proven pulmonary Langerhans' cell histiocytosis in whom radiologic improvement occurred following smoking cessation. The patients had 23- and 25-pack-year smoking histories, respectively. High-resolution CT revealed multiple small nodules, located predominantly in the upper and middle lung fields. There was a close temporal relationship between smoking cessation and radiologic improvement.
M W Brauner, P Grenier, K Tijani, J P Battesti, D Valeyre
Pulmonary Langerhans cell histiocytosis: evolution of lesions on CT scans.
Radiology. 1997 Aug;204(2):497-502. doi: 10.1148/radiology.204.2.9240543.
Abstract/Text
PURPOSE: To document the evolution of pulmonary lesions of Langerhans cell histiocytosis (LCH) with sequential computed tomography (CT).
MATERIALS AND METHODS: Initial and final CT scans of 21 patients with LCH and CT evidence of pulmonary disease were compared retrospectively. Histologic confirmation of pulmonary involvement was available in 11 patients.
RESULTS: On initial CT images, a nodular pattern (n = 14) was seen more frequently than a cystic pattern (n = 7). On final CT images, a cystic pattern (n = 14) was seen more often than a nodular one (n = 6). There was complete resolution of parenchymal abnormality in one case. Nodular opacities, thick-walled cysts, and ground-glass opacities underwent regression. Thin-walled cysts, linear opacities, and emphysematous lesions remained unchanged or progressed.
CONCLUSION: Pulmonary CT allows good assessment of the evolution of LCH lesions. Nodular lesions probably represent active disease and often undergo regression or transform into cysts.
Hyo Jin Kim, Kyung Soo Lee, Takeshi Johkoh, Noriyuki Tomiyama, Ho Yun Lee, Joungho Han, Tae Sung Kim
Pulmonary Langerhans cell histiocytosis in adults: high-resolution CT-pathology comparisons and evolutional changes at CT.
Eur Radiol. 2011 Jul;21(7):1406-15. doi: 10.1007/s00330-011-2075-9. Epub 2011 Feb 11.
Abstract/Text
OBJECTIVE: To compare high-resolution (HR) CT and histopathological findings and to evaluate serial CT findings in pulmonary Langerhans cell histiocytosis (PLCH).
METHODS: We reviewed CT of lung lesions in 27 adults (M:F = 20:7, mean age, 41 ± 12.3 years) with PLCH. After evaluating lung abnormalities including nodules, micronodules, thick-walled, thin-walled, and bizarre-shaped cysts and reticulation, observers compared CT findings obtained at lung biopsy sites with histopathological findings. The final CT was compared with the initial CT to determine disease extent changes.
RESULTS: The most frequently observed patterns of lung abnormalities were micronodules (n = 24, 89%), thick-walled (n = 22, 82%), and thin-walled (n = 22, 82%) cysts. Even thin-walled and bizarre cysts harboured active inflammatory Langerhans cell sheets and eosinophils in their walls. In thin-walled cysts, we noted pericystic inflammatory cell infiltrations along the alveolar walls, as well as pericystic emphysema. Thin-walled or bizarre cysts demonstrated a tendency to coalesce with surrounding cysts via their cystic wall destruction. Fourteen (52%) patients showed improvement and nine (33%) showed progressing disease.
CONCLUSION: More than half of patients with pulmonary PLCH show improvement at follow-up CT. Even thin-walled cysts harbour active inflammatory cells on histopathology and exhibit improvement at follow-up CT.
R Watanabe, K Tatsumi, S Hashimoto, A Tamakoshi, T Kuriyama, Respiratory Failure Research Group of Japan
Clinico-epidemiological features of pulmonary histiocytosis X.
Intern Med. 2001 Oct;40(10):998-1003.
Abstract/Text
OBJECTIVE: To define the clinico-epidemiological features of pulmonary histiocytosis X in Japan.
METHODS: A nationwide survey was carried out in 1997 using two questionnaires.
RESULTS: The first questionnaire, which attempted to determine the number of patients during 1996, revealed that the number of patients treated at hospitals with 200 or more beds during the one-year period was estimated to be 160 (95% confidence interval: 140-180). The estimated crude prevalence among those aged 16 to 70 years was calculated as 0.27 and 0.07 per 100,000 population in males and females, respectively. The second questionnaire was concerned with the clinico-epidemiological features of the disease. Seventy-three histologically diagnosed patients were evaluated. It primarily afflicted younger adults, between the ages of 20 and 50, and showed a male predominance. Over 90% of the patients were smokers or ex-smokers and over 50% started smoking before 20 years of age, suggesting a strong association with cigarette smoking. Steroid therapy was applicable to 34% of the patients. In the patients who received steroid therapy, regression and stabilization were observed in 28% and deterioration in 36%. As for the patients for whom steroids were not required, remission occurred in 63% and progression in 10%. The ratio of remissions plus stabilization was higher in the patients who were not treated with steroids compared with those who required steroid therapy (p<0.05).
CONCLUSION: In patients with pulmonary histiocytosis X therapeutic results obtained with steroids seemed not to be encouraging, although steroids are thought to be the most plausible treatment.
R S Crausman, C A Jennings, R M Tuder, L M Ackerson, C G Irvin, T E King
Pulmonary histiocytosis X: pulmonary function and exercise pathophysiology.
Am J Respir Crit Care Med. 1996 Jan;153(1):426-35. doi: 10.1164/ajrccm.153.1.8542154.
Abstract/Text
Pulmonary histiocytosis X (PHX) is a diffuse, smoking-related lung disease characterized pathologically by bronchocentric inflammation, cyst formation, and widespread vascular abnormalities and physiologically by exercise limitation. The major mechanism underlying exercise impairment in this disease has not been previously defined. Spirometry, lung volumes, lung mechanics, and exercise physiology were performed on 23 patients with PHX. Two subgroups were identified on the basis of elastic recoil: 12 subjects had an elevated coefficient of elastic recoil with 11 demonstrating a predominant pattern of restriction, and 10 subjects had normal elastic recoil and relatively normal lung function. Exercise performance was severely limited in both subgroups (workload 53 +/- 3%). Abnormalities of ventilatory function and gas exchange were present but did not appear to be exercise-limiting in the majority of subjects. Indices reflecting pulmonary vascular function (DLCO, baseline VD/VT, exercise VD/VT) were abnormal. Strong correlations between overall exercise performance (% predicted VO2max) and indices of vascular involvement were present: DLCO (r = 0.68, p = 0.0004), baseline VD/VT (-0.65, 0.001), exercise VD/VT (-0.67, 0.0004). Similar correlations were found when exercise performance was measured by maximal workload achieved. We conclude that (1) subjects with PHX present with either normal or predominantly restrictive pulmonary physiology and that (2) exercise impairment is common and appears to reflect pulmonary vascular dysfunction.
Abdellatif Tazi, Karima Marc, Stéphane Dominique, Cédric de Bazelaire, Bruno Crestani, Thierry Chinet, Dominique Israel-Biet, Jacques Cadranel, Jacques Frija, Gwenael Lorillon, Dominique Valeyre, Sylvie Chevret
Serial computed tomography and lung function testing in pulmonary Langerhans' cell histiocytosis.
Eur Respir J. 2012 Oct;40(4):905-12. doi: 10.1183/09031936.00210711. Epub 2012 Mar 22.
Abstract/Text
Little is known about longitudinal lung function variation in patients with pulmonary Langerhans' cell histiocytosis (LCH). The contribution of serial lung computed tomography (CT) to managing these patients has not been evaluated. This long-term retrospective study included 49 patients who were serially evaluated by lung CT and pulmonary function tests. The lung function variation was categorised as improvement or deterioration. The extent of the CT lesions was correlated with lung function. Lung function deteriorated in ∼60% of the patients. Forced expiratory volume in 1 s (FEV(1)) and diffusing capacity of the lung for carbon monoxide (D(L,CO)) were the parameters that most frequently deteriorated. A subgroup of patients experienced a dramatic decline in FEV(1) within 2 yrs of diagnosis. Airway obstruction was the major functional pattern observed. In a multivariate analysis, % predicted FEV(1)at diagnosis was the only factor associated with the incidence of airway obstruction. The increase in cystic lesions on the lung CTs was associated with impaired lung function but did not anticipate the decline in FEV(1) or D(L,CO). Serial lung function tests are essential for following patients with pulmonary LCH, who frequently develop airway obstruction. A lung CT at diagnosis is informative, but routine sequential CTs seem less useful. A prospective study is needed to characterise those patients with early progressive disease.
Matthieu Canuet, Romain Kessler, Mi-Young Jeung, Anne-Cécile Métivier, Ari Chaouat, Emmanuel Weitzenblum
Correlation between high-resolution computed tomography findings and lung function in pulmonary Langerhans cell histiocytosis.
Respiration. 2007;74(6):640-6. doi: 10.1159/000106843. Epub 2007 Aug 3.
Abstract/Text
BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon interstitial lung disease which can lead to serious respiratory failure. The correlation between high-resolution computed tomography (HRCT) findings and lung function have not been studied in depth.
OBJECTIVES: To assess the relationship between HRCT findings and lung function in PLCH.
METHODS: Since HRCT abnormalities in PLCH consist mainly of nodular opacities and cystic abnormalities, we determined semiquantitative scores of nodular profusion and cystic extent. We therefore assessed the relationship between HRCT abnormalities on one hand and lung function and gas exchange parameters on the other, in patients with PLCH.
RESULTS: In our series of 26 consecutive patients, we found no significant correlation between the score of nodular profusion and lung function or gas exchange parameters. The score of cystic extent showed a quite strong and significant correlation with FEV(1)/FVC (r = -0.62; p = 0.01), but also with PaO(2) (r = -0.69; p = 0.001) and carbon monoxide diffusing capacity (r = -0.60; p < 0.01). Furthermore, the patients with a predominant cystic pattern (n = 7) had the highest grade of dyspnea on exertion (p = 0.004), the lowest FEV(1)/FVC ratio (p = 0.02) and the lowest PaO(2) (p = 0.02) compared to patients with a predominant nodular (n = 12) or a mixed pattern (n = 7).
CONCLUSIONS: We conclude that in PLCH, the cystic extent on HRCT, but not the nodular profusion, correlates significantly with lung function abnormalities and impairment of gas exchange.
(c) 2007 S. Karger AG, Basel.
S Chollet, P Soler, P Dournovo, M S Richard, V J Ferrans, F Basset
Diagnosis of pulmonary histiocytosis X by immunodetection of Langerhans cells in bronchoalveolar lavage fluid.
Am J Pathol. 1984 May;115(2):225-32.
Abstract/Text
Based on the finding that Langerhans cells and histiocytosis X cells react with the monoclonal antibody OKT6, raised against a subset of thymocytes, we used this antibody to study the cells collected by bronchoalveolar lavage (BAL) from 131 patients, including 18 with pulmonary histiocytosis X, 43 with pulmonary sarcoidosis, 67 with miscellaneous pulmonary disorders, and 3 controls. Immunofluorescence studies demonstrated the presence of OKT6-reactive cells in all patients with pulmonary histiocytosis X (mean +/- SEM, 5.29% +/- 1.14% of all cells in BAL fluid). Immunoelectron microscopic studies revealed that the cells labeled in these patients (n = 13) contained Langerhans granules. The number of fluorescent cells in the other 113 patients was significantly smaller (mean +/- SEM, 0.20% +/- 0.04% of all cells; P less than 0.001). In the 3 control patients, in the 43 patients with sarcoidosis, and in 61 of the 67 patients with miscellaneous disorders unrelated to histiocytosis X, no cells or less than 1% of the total were labeled; however, in the 6 remaining patients in this miscellaneous group, 1.3 to 2.8% of all cells in BAL were labeled. In 3 of these 6 patients, immunoelectronmicroscopic examination showed that the cells labeled by OKT6 had the general characteristics of Langerhans cells but lacked Langerhans granules. OKT3, OKT4, and OKT8 monoclonal antibodies did not stain histiocytosis X cells in BAL fluid.
U Auerswald, J Barth, H Magnussen
Value of CD-1-positive cells in bronchoalveolar lavage fluid for the diagnosis of pulmonary histiocytosis X.
Lung. 1991;169(6):305-9.
Abstract/Text
Pulmonary histiocytosis X is characterized by an accumulation of CD-1-positive histiocytosis X cells in the lung, which also can be found in the bronchoalveolar lavage fluid (BALF). However, it has recently been demonstrated that CD-1-positive cells can also be detected in BALF of patients with other interstitial lung diseases and in healthy smokers. We therefore examined the frequency of CD-1-positive cells in a pool of patients with different pulmonary disorders, according to their smoking habits and diagnoses. We have studied the bronchoalveolar lavage in patients with pulmonary histiocytosis X (n = 6), sarcoidosis (n = 88), and in 97 patients with other miscellaneous lung disorders by using the immunoperoxidase method to detect CD-1-positive cells on glass slides. All patients with histologically proven histiocytosis X displayed more than 5% CD-1-positive cells, whereas patients with other pulmonary disorders showed no more than 3.6% CD-1-positive BAL cells. The dividing line of 5% CD-1-positive cells was not influenced by patients' smoking habits. The identification of CD-1-positive cells in BALF appears to be useful in diagnosing pulmonary histiocytosis X.
A J Hance
Pulmonary immune cells in health and disease: dendritic cells and Langerhans' cells.
Eur Respir J. 1993 Sep;6(8):1213-20.
Abstract/Text
The activation of T-lymphocytes recognizing specific antigens is a crucial and early event in the development of an immune response, but T-lymphocytes cannot respond to antigens without help of a second cell type called accessory cells or antigen-presenting cells. Studies from several groups have indicated that pulmonary dendritic cells and Langerhans' cells, like their counterparts in other tissues, are potent accessory cells, and suggest that these cells may play an extremely important role in initiating lung immune responses. The purpose of this review is to summarize current information concerning pulmonary dendritic cells and Langerhans' cells, including their origin, distribution in the lung and functional capabilities. The possible role of these cells in certain lung diseases of immune origin will also be discussed.
Antonella Caminati, Sergio Harari
Smoking-related interstitial pneumonias and pulmonary Langerhans cell histiocytosis.
Proc Am Thorac Soc. 2006 Jun;3(4):299-306. doi: 10.1513/pats.200512-135TK.
Abstract/Text
The relationship between cigarette smoke and interstitial lung diseases (ILDs) is not clear. Respiratory bronchiolitis (RB), usually found as an incidental histologic abnormality in otherwise asymptomatic smokers, is characterized by the accumulation of cytoplasmic golden-brown-pigmented macrophages within respiratory bronchioles. A small proportion of smokers have a more exaggerated response that, in addition to the bronchiole-centered lesions, provokes interstitial and air space inflammation and fibrosis extending to the nearby alveoli. This set of histologic changes is called RB-ILD, and results in clinical symptoms. Desquamative interstitial pneumonia (DIP) is characterized by panlobular involvement, diffuse mild-to-moderate interstitial fibrosis, and massive alveolar filling with macrophages. It is well known that the histopathologic patterns of RB-ILD and DIP may overlap, and that the key features for differentiating these disorders are the distribution and the extent of the lesions: bronchiolocentric in RB-ILD and diffuse in DIP. It has been proposed that RB, RB-ILD, and DIP may be different components of the same histopathologic disease spectrum, representing various degrees of severity of the same process caused by chronic smoking, although this is still controversial. Pulmonary Langerhans' cell histiocytosis is also strongly related to cigarette smoking and is characterized by the proliferation of specific histiocytes, known as Langerhans' cells, and their infiltration of organ systems. Although RB, RB-ILD, DIP, and Pulmonary Langerhans' cell histiocytosis are considered as discrete entities of smokers, it is not infrequent to find a mixture of pathologic features rendering the histopathologic diagnosis difficult.
A Delobbe, J Durieu, A Duhamel, B Wallaert
Determinants of survival in pulmonary Langerhans' cell granulomatosis (histiocytosis X). Groupe d'Etude en Pathologie Interstitielle de la Société de Pathologie Thoracique du Nord.
Eur Respir J. 1996 Oct;9(10):2002-6.
Abstract/Text
The course of pulmonary Langerhans' cell granulomatosis (pulmonary LCG) is variable, difficult to predict and ranges from spontaneous remission to progressive respiratory insufficiency and death. To identify the determinants of survival, we performed a survival analysis on 45 patients with pulmonary LCG. The patients were aged 28 +/- 10 yrs (mean +/- SD) (range 12-62 yrs), 32 males and 13 females, almost exclusively current smokers (96%), and 78% presented symptoms at the time of diagnosis. Diagnosis was made by lung biopsy in 25 patients (56%) and by bronchoalveolar lavage (BAL) analysis in 20 patients (44%). The patients were followed for a median period of 6 yrs (range 1-29 yrs) after the diagnosis. During the period of observation, 33 (73%) patients survived (median follow-up period = 5.8 yrs; range, 1-29 yrs) and 12 (27%) died or underwent lung transplantation (median follow-up period = 8.4 yrs; range 1.4 - 16.1 yrs). The median survival was approximately 13 years. A univariate analysis demonstrated that diminished survival was significantly associated with: an older age at diagnosis (p = 0.0001); a lower forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio at diagnosis (p = 0.005); a higher residual volume/total lung volume (RV/TLC) ratio at diagnosis (p = 0.02); and steroid therapy during follow-up (p = 0.03). Additional predictive information on mortality was: age > 26 yrs (sensitivity 83%, specificity 64%); FEV1/FVC ratio < 0.66 (sensitivity 75%, specificity 86%); and a RV/TLC ratio > 0.33 (sensitivity 75%, specificity 63%). In multivariate Cox analysis, the combination of factors which gave the best prognostic value was FEV1/FVC ratio and age (p < 0.01). The present findings suggest that adverse prognosis factors at diagnosis in pulmonary Langerhans' cell granulomatosis include older age, lower FEV1/FVC ratio and higher RV/TLC ratio, with additional predictive information on mortality if aged > 26 yrs, FEV1/FVC ratio < 0.66, and RV/TLC ratio > 0.33.
A Tazi, L Montcelly, A Bergeron, D Valeyre, J P Battesti, A J Hance
Relapsing nodular lesions in the course of adult pulmonary Langerhans cell histiocytosis.
Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 1):2007-10. doi: 10.1164/ajrccm.157.6.9709026.
Abstract/Text
In most patients with pulmonary Langerhans cell histiocytosis (LCH), clinical and radiological abnormalities initially either stabilize or regress, often without treatment. Little information is available, however, concerning the subsequent evolution of disease in patients who initially follow a benign course. We describe four patients with biopsy-confirmed pulmonary LCH whose initial course was characterized by regression of parenchymal nodular lesions, but who subsequently developed one or more episodes of active disease 7 mo to 7.5 yr after their initial presentation. In each case, the subsequent episodes of active disease were characterized by the reappearance or marked increase in nodular radiographic abnormalities, whose presence was confirmed by high-resolution computed tomography (HRCT). Thus, initial regression of nodular lesions in pulmonary LCH does not preclude the reappearance of one or more episodes of active disease, and may have important consequences on the long-term prognosis of these patients.
R Vassallo, J H Ryu, T V Colby, T Hartman, A H Limper
Pulmonary Langerhans'-cell histiocytosis.
N Engl J Med. 2000 Jun 29;342(26):1969-78. doi: 10.1056/NEJM200006293422607.
Abstract/Text
Gwenaël Lorillon, Abdellatif Tazi
How I manage pulmonary Langerhans cell histiocytosis.
Eur Respir Rev. 2017 Sep 30;26(145). doi: 10.1183/16000617.0070-2017. Epub 2017 Sep 6.
Abstract/Text
Pulmonary Langerhans cell histiocytosis (PLCH) is a rare sporadic cystic lung disease of unknown aetiology that is characterised by the infiltration and destruction of the wall of distal bronchioles by CD1a+ Langerhans-like cells. In adults, PLCH is frequently isolated and affects young smokers of both sexes. Recent multicentre studies have led to the more standardised management of patients in clinical practice. Smoking cessation is essential and is occasionally the only suitable intervention. Serial lung function testing is important because a significant proportion of patients may experience an early decline in forced expiratory volume in 1 s and develop airflow obstruction. Cladribine was reported to dramatically improve progressive PLCH in some patients. Its efficacy and tolerance are currently being evaluated. Patients who complain of unexplained dyspnoea with decreased diffusing capacity of the lung for carbon monoxide should be screened for pulmonary hypertension by Doppler echocardiography, which must be confirmed by right heart catheterisation. Lung transplantation is a therapeutic option for patients with advanced PLCH.The identification of the BRAFV600E mutation in approximately half of Langerhans cell histiocytosis lesions, including PLCH, and other mutations of the mitogen-activated protein kinase (MAPK) pathway in a subset of lesions has led to targeted treatments (BRAF and MEK (MAPK kinase) inhibitors). These treatments need to be rigorously evaluated because of their potentially severe side-effects.
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